U.S. patent application number 10/170558 was filed with the patent office on 2003-03-06 for 6-(aryl-amido or aryl-amidomethyl)-naphthalen-2-yloxy-acidic derivatives as inhibitors of plasminogen activator inhibitor type-1 (pai-1).
This patent application is currently assigned to Wyeth. Invention is credited to Commons, Thomas Joseph, Crandall, David LeRoy, Croce, Susan Christman, Elokdah, Hassan Mohmoud, Trybulski, Eugene John, Woodworth, Richard Page.
Application Number | 20030045560 10/170558 |
Document ID | / |
Family ID | 26971330 |
Filed Date | 2003-03-06 |
United States Patent
Application |
20030045560 |
Kind Code |
A1 |
Commons, Thomas Joseph ; et
al. |
March 6, 2003 |
6-(Aryl-amido or aryl-amidomethyl)-naphthalen-2-yloxy-acidic
derivatives as inhibitors of plasminogen activator inhibitor type-1
(PAI-1)
Abstract
This invention provides novel compounds, pharmaceutical
compositions and methods of treating thrombotic disorders in
mammals, the compounds having the formula: 1 Wherein: Ar is phenyl,
naphthyl, furanyl, benzofuranyl, indolyl, pyrazolyl, oxazolyl,
fluorenyl, phenylcycloalkane where the cycloalkane can be
cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl and Ar can be
optionally substituted by 1 to 3 groups selected from
C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxy, hydroxy,
phenyl-(CH.sub.2).sub.0-6--, phenyl-(CH.sub.2).sub.0-6O--,
C.sub.3-C.sub.6 cycloalkyl, --(CH.sub.2)--C.sub.3-C.sub.6
cycloalkyl, halogen, C.sub.1-C.sub.3 perflouroalkyl and
C.sub.1-C.sub.3 perfluoroalkoxy where phenyl can be substituted
with from 1 to 3 groups selected from C.sub.1-C.sub.6 alkyl,
C.sub.1-C.sub.6 alkoxy, phenyl, halogen, trifluoromethyl or
trifluoromethoxy; R.sub.1 is hydrogen, C.sub.1-C.sub.6 alkyl or
phenyl-(CH.sub.2).sub.1-6-- where phenyl can be substituted with
C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxy, halo,
trifluoromethyl or trifluoromethoxy; R.sub.2 and R.sub.3 are H,
C.sub.1-C.sub.6 alkyl, phenyl-(CH.sub.2).sub.0-3--, halo and
C.sub.1-C.sub.3 perfluoroalkyl where phenyl can be substituted with
C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxy, halo,
trifluoromethyl or trifluoromethoxy; R.sub.4 is
--CHR.sub.5CO.sub.2H or --CH.sub.2-tetrazole where R.sub.5 is H or
benzyl; and n=0 or 1; or a pharmaceutically acceptable salt or
ester form thereof.
Inventors: |
Commons, Thomas Joseph;
(Wayne, PA) ; Croce, Susan Christman;
(Lambertville, NJ) ; Woodworth, Richard Page;
(Eagleville, PA) ; Trybulski, Eugene John;
(Princeton Junction, NJ) ; Elokdah, Hassan Mohmoud;
(Yardley, PA) ; Crandall, David LeRoy;
(Doylestown, PA) |
Correspondence
Address: |
Wyeth
5 Giralda Farms
Madison
NJ
07940
US
|
Assignee: |
Wyeth
Madison
NJ
|
Family ID: |
26971330 |
Appl. No.: |
10/170558 |
Filed: |
June 13, 2002 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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60308656 |
Jul 30, 2001 |
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60299652 |
Jun 20, 2001 |
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Current U.S.
Class: |
514/381 ;
514/374; 514/406; 514/419; 514/469; 514/563; 548/248; 548/252;
548/374.1; 548/494; 549/444; 562/450 |
Current CPC
Class: |
C07D 403/12 20130101;
C07D 307/68 20130101; C07C 235/48 20130101; A61P 9/10 20180101;
C07D 405/12 20130101; C07D 209/42 20130101; C07C 233/73 20130101;
C07D 307/84 20130101; A61P 7/02 20180101; C07D 231/14 20130101;
A61P 3/10 20180101; C07C 2601/14 20170501; C07D 307/85 20130101;
C07C 2601/08 20170501 |
Class at
Publication: |
514/381 ;
514/374; 514/406; 514/419; 514/469; 514/563; 548/248; 548/252;
548/374.1; 548/494; 549/444; 562/450 |
International
Class: |
C07D 261/18; C07D 43/02;
A61K 031/421; A61K 031/415; A61K 031/195 |
Claims
What is claimed:
1. A compound of the formula: 15Wherein: Ar is phenyl, naphthyl,
furanyl, benzofuranyl, indolyl, pyrazolyl, oxazolyl, fluorenyl,
phenylcycloalkane where the cycloalkane can be cyclopropyl,
cyclobutyl, cyclopentyl or cyclohexyl and Ar can be optionally
substituted by from 1 to 3 groups selected from C.sub.1-C.sub.6
alkyl, C.sub.1-C.sub.6 alkoxy, hydroxy,
phenyl-(CH.sub.2).sub.0-6--, phenyl-(CH.sub.2).sub.0-6O--,
C.sub.3-C.sub.6 cycloalkyl, --(CH.sub.2)--C.sub.3-C.sub.6
cycloalkyl, halogen, C.sub.1-C.sub.3 perflouroalkyl and
C.sub.1-C.sub.3 perfluoroalkoxy where phenyl can be substituted
with from 1 to 3 groups selected from C.sub.1-C.sub.6 alkyl,
C.sub.1-C.sub.6 alkoxy, phenyl, halogen, trifluoromethyl or
trifluoromethoxy; R.sub.1 is hydrogen, C.sub.1-C.sub.6 alkyl or
phenyl-(CH.sub.2).sub.1-6-- where phenyl can be substituted with
C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxy, halogen,
trifluoromethyl or trifluoromethoxy. R.sub.2 and R.sub.3 are
independently hydrogen, C.sub.1-C.sub.6 alkyl,
phenyl-(CH.sub.2).sub.0-3-- -, halogen and C.sub.1-C.sub.3
perfluoroalkyl where phenyl can be substitute with C.sub.1-C.sub.6
alkyl, C.sub.1-C.sub.6 alkoxy, halogen, trifluoromethyl or
trifluoromethoxy. R.sub.4 is --CHR.sub.5CO.sub.2H or
--CH.sub.2-tetrazole where R.sub.5 is hydrogen or benzyl; and n=0
or 1; or a pharmaceutically acceptable salt or ester form
thereof.
2. A compound of claim 1 of the formulae 1 or 2: 16R.sub.1 is
hydrogen, C.sub.1-C.sub.6 alkyl or phenyl-(CH.sub.2).sub.1-6--
where phenyl can be substituted with C.sub.1-C.sub.6 alkyl,
C.sub.1-C.sub.6 alkoxy, halogen, trifluoromethyl or
trifluoromethoxy. R.sub.2 and R.sub.3 are independently hydrogen,
C.sub.1-C.sub.6 alkyl, phenyl-(CH.sub.2).sub.0-3-- -, halogen and
C.sub.1-C.sub.3 perfluoroalkyl where phenyl can be substitute with
C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxy, halogen,
trifluoromethyl or trifluoromethoxy. R.sub.4 is
--CHR.sub.5CO.sub.2H or --CH.sub.2-tetrazole; R.sub.5 is hydrogen
or benzyl; R.sub.6 is selected from C.sub.1-C.sub.6 alkyl,
C.sub.1-C.sub.6 alkoxy, hydroxy, phenyl-(CH.sub.2).sub.0-6--,
phenyl-(CH.sub.2).sub.0-6O--, C.sub.3-C.sub.6, cycloalkyl, halogen,
C.sub.1-C.sub.3 perflouroalkyl and C.sub.1-C.sub.3 perfluoroalkoxy;
where the phenyl ring in these R.sub.6 groups can be substituted
with C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxy,
phenyl-(CH.sub.2).sub.0-3--, halogen, trifluoromethyl or
trifluoromethoxy; or a pharmaceutically acceptable salt or ester
form thereof.
3. A compound of claim 1 of the formula: 17wherein: Ar is a moiety
selected from the group of: 18R.sub.1 is hydrogen, C.sub.1-C.sub.6
alkyl or phenyl-(CH.sub.2).sub.1-6-- where phenyl can be
substituted with C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxy,
halogen, trifluoromethyl or trifluoromethoxy. R.sub.2 and R.sub.3
are independently hydrogen, C.sub.1-C.sub.6 alkyl,
phenyl-(CH.sub.2).sub.0-3--, halogen and C.sub.1-C.sub.3
perfluoroalkyl where phenyl can be substitute with C.sub.1-C.sub.6
alkyl, C.sub.1-C.sub.6 alkoxy, halogen, trifluoromethyl or
trifluoromethoxy. R.sub.4 is --CHR.sub.5CO.sub.2H or
--CH.sub.2-tetrazole; R.sub.5 is hydrogen or benzyl; R.sub.7 is
selected from C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxy,
hydroxy, phenyl-(CH.sub.2).sub.0-6--, phenyl-(CH.sub.2).sub.0-6O--,
C.sub.3-C.sub.6 cycloalkyl, halogen, C.sub.1-C.sub.3 perflouroalkyl
and C.sub.1-C.sub.3 perfluoroalkoxy; where the phenyl ring in these
R.sub.7 groups can be substituted with C.sub.1-C.sub.6 alkyl,
C.sub.1-C.sub.6 alkoxy, phenyl, halogen, trifluoromethyl or
trifluoromethoxy; R.sub.8 and R.sub.9 are each independently
selected from H, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxy,
phenyl-(CH.sub.2).sub.0-3--, halogen, trifluoromethyl or
trifluoromethoxy; or a pharmaceutically acceptable salt or ester
form thereof.
4. A compound of claim 1 of the formula: 19wherein: R.sub.1 is
hydrogen, C.sub.1-C.sub.6 alkyl or phenyl-(CH.sub.2).sub.1-6--
where phenyl can be substituted with C.sub.1-C.sub.6 alkyl,
C.sub.1-C.sub.6 alkoxy, halogen, trifluoromethyl or
trifluoromethoxy. R.sub.2 and R.sub.3 are independently hydrogen,
C.sub.1-C.sub.6 alkyl, phenyl-(CH.sub.2).sub.0-3-- -, halogen and
C.sub.1-C.sub.3 perfluoroalkyl where phenyl can be substituted with
C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxy, halogen,
trifluoromethyl or trifluoromethoxy. R.sub.4 is
--CHR.sub.5CO.sub.2H or --CH.sub.2-tetrazole; R.sub.5 is hydrogen
or benzyl; R.sub.7 is selected from C.sub.1-C.sub.6 alkyl,
C.sub.1-C.sub.6 alkoxy, hydroxy, phenyl-(CH.sub.2).sub.0-6--,
phenyl-(CH.sub.2).sub.0-6O--, C.sub.3-C.sub.6, cycloalkyl, halogen,
C.sub.1-C.sub.3 perflouroalkyl and C.sub.1-C.sub.3 perfluoroalkoxy;
where the phenyl ring in these R.sub.7 groups can be substituted
with C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxy,
phenyl-(CH.sub.2).sub.0-3--, halogen, trifluoromethyl or
trifluoromethoxy; R.sub.8 and R.sub.9 are each independently
selected from H, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxy,
phenyl, halogen, trifluoromethyl or trifluoromethoxy; or a
pharmaceutically acceptable salt or ester form thereof.
5. A compound of claim 1 of the formula: 20wherein: R.sub.1 is
hydrogen, C.sub.1-C.sub.6 alkyl or phenyl-(CH.sub.2).sub.1-6--
where phenyl can be substituted with C.sub.1-C.sub.6 alkyl,
C.sub.1-C.sub.6 alkoxy, halogen, trifluoromethyl or
trifluoromethoxy. R.sub.2 and R.sub.3 are independently hydrogen,
C.sub.1-C.sub.6 alkyl, phenyl-(CH.sub.2).sub.0-3-- -, halogen and
C.sub.1-C.sub.3 perfluoroalkyl where phenyl can be substitute with
C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxy, halogen,
trifluoromethyl or trifluoromethoxy. R.sub.4 is
--CHR.sub.5CO.sub.2H or --CH.sub.2-tetrazole; R.sub.5 is hydrogen
or benzyl; R.sub.10 is selected from C.sub.1-C.sub.6 alkyl,
C.sub.1-C.sub.6 alkoxy, hydroxy, C.sub.3-C.sub.6, cycloalkyl,
halogen, C.sub.1-C.sub.3 perflouroalkyl and C.sub.1-C.sub.3
perfluoroalkoxy; R.sub.11 is selected from C.sub.1-C.sub.6 alkyl,
phenyl-(CH.sub.2).sub.0-6--, C.sub.3-C.sub.6 cycloalkyl, or
--(CH.sub.2)--C.sub.3-C.sub.6 cycloalkyl; where the phenyl ring in
these R.sub.7 groups can be substituted with C.sub.1-C.sub.6 alkyl,
C.sub.1-C.sub.6 alkoxy, phenyl, halogen, trifluoromethyl or
trifluoromethoxy; Or a pharmaceutically acceptable salt or ester
form thereof.
6. A compound of claim 1 of the formula: 21wherein: R.sub.1 is
hydrogen, C.sub.1-C.sub.6 alkyl or phenyl-(CH.sub.2).sub.1-6--
where phenyl can be substituted with C.sub.1-C.sub.6 alkyl,
C.sub.1-C.sub.6 alkoxy, halogen, trifluoromethyl or
trifluoromethoxy. R.sub.2 and R.sub.3 are independently hydrogen,
C.sub.1-C.sub.6 alkyl, phenyl-(CH.sub.2).sub.0-3-- -, halogen and
C.sub.1-C.sub.3 perfluoroalkyl where phenyl can be substitute with
C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxy, halogen,
trifluoromethyl or trifluoromethoxy. R.sub.4 is
--CHR.sub.5CO.sub.2H or --CH.sub.2-tetrazole; R.sub.5 is hydrogen
or benzyl; R.sub.8 and R.sub.9 are each independently selected from
H, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxy, phenyl, halogen,
trifluoromethyl or trifluoromethoxy; or a pharmaceutically
acceptable salt or ester form thereof.
7. A compound of claim 1 which is selected from the group of:
(6-{[Benzofuran-2-carbonyl)-amino]-methyl}-naphthalen-2-yloxy)-acetic
acid; Benzofuran-2-carboxylic acid
[6-(2H-tetrazol-5-ylmethoxy-naphthalen- -2-ylmethyl]-amide;
2-Butyl-benzofuran-3-carboxylic acid
[6-(2H-tetrazol-5-ylmethoxy)-naphthalen-2-yl]-amide;
{6-[(2-Butyl-benzofuran-3-carbonyl)-amino]-naphthalen-2-yloxy}-acetic
acid; or 2-Butyl-benzofuran-3-carboxylic acid
[5-bromo-6-(2H-tetrazol-5-y- lmethoxy)-naphthalen-2-yl]-amide; or a
pharmaceutically acceptable salt or ester form thereof.
8. A compound of claim 1 which is selected from the group of:
{1-Bromo-6-[(2-butyl-benzofuran-3-carbonyl)-amino]-naphthalen-2-yloxy}-ac-
etic acid;
2-{1-Bromo-6-[(2-butyl-benzofuran-3-carbonyl)-amino]-naphthalen-
-2-yloxy}-3-phenyl-propionic acid; 2-Butyl-benzofuran-3-carboxylic
acid [6-(1H-tetrazol-5-ylmethoxy)-naphthalen-2-ylmethyl]-amide;
(6-{[(2-butyl-benzofuran-3-carbonyl)-amino]-methyl}-naphthalen-2-yloxy)-a-
cetate;
[6-({[5-(4-Chloro-phenyl)-2-methyl-furan-3-carbonyl]-amino}-methyl-
)-naphthalen-2-yloxy]-acetic acid; or
[6-({[5-(4-Chloro-phenyl)-2-trifluor-
omethyl-furan-3-carbonyl]-amino}-methyl)-naphthalen-2-yloxy]-acetic
acid; or a pharmaceutically acceptable salt or ester form
thereof.
9. A compound of claim 1 which is selected from the group of:
(6-{[(1-phenyl-5-propyl-1H-pyrazole-4-carbonyl)-amino]-methyl}-naphthalen-
-2-yloxy)-acetic acid;
[6-({[1-(4-Chloro-phenyl)-5-propyl-1H-pyrazole-4-ca-
rbonyl]-amino}-methyl)-naphthalen-2-yloxy]-acetic acid;
[6-({[1-(4-Chloro-phenyl)-5-trifluoromethyl-1H-pyrazole-4-carbonyl]-amino-
}-methyl)-naphthalen-2-yloxy]-acetic acid;
(1-Bromo-6-{[(1-phenyl-5-propyl-
-1H-pyrazole-4-carbonyl)-amino]-methyl}-naphthalen-2-yloxy)-acetic
acid; or
[1-Bromo-6-({[1-(4-chloro-phenyl)-5-trifluoromethyl-1H-pyrazole-4-carb-
onyl]-amino}-methyl)-naphthalen-2-yloxy]-acetic acid.
10. A compound of claim 1 which is selected from the group of:
2-Butyl-benzofuran-3-carboxylic acid
[5-bromo-6-(1H-tetrazol-5-ylmethoxy)-
-naphthalen-2-ylmethyl]-amide;
2-(1-Bromo-6-{[(2-butyl-benzofuran-3-carbon-
yl)-amino]-methyl}-naphthalen-2-yloxy)-3-phenyl-propionic acid;
(1-bromo-6-{[(2-butyl-benzofuran-3-carbonyl)-amino]-methyl}-naphthalen-2--
yloxy)-acetate; 2-Methyl-benzofuran-3-carboxylic acid
[5-bromo-6-(1H-tetrazol-5-ylmethoxy)-naphthalen-2-ylmethyl]-amide;
or 2-Ethyl-benzofuran-3-carboxylic acid
[5-bromo-6-(1H-tetrazol-5-ylmethoxy)-
-naphthalen-2-ylmethyl]-amide; or a pharmaceutically acceptable
salt or ester form thereof.
11. A compound of claim 1 which is selected from the group of:
1-Phenyl-5-propyl-1H-pyrazole-4-carboxylic acid
[5-bromo-6-(1H-tetrazol-5-
-ylmethoxy)-naphthalen-2-ylmethyl]-amide;
2-Butyl-benzofuran-3-carboxylic acid
[6-(1H-tetrazol-5-ylmethoxy)-5-p-tolyl-naphthalen-2-ylmethyl]-amide;
2-Butyl-benzofuran-3-carboxylic acid
[5-phenyl-6-(1H-tetrazol-5-ylmethoxy-
)-naphthalen-2-ylmethyl]-amide; 2-Butyl-benzofuran-3-carboxylic
[5-(4-methoxy
phenyl)-6-(1H-tetrazol-5-ylmethoxy)-naphthalen-2-ylmethyl]-- amide;
or 2-Butyl-benzofuran-3-carboxylic acid
[5-(4-chloro-phenyl)-6-(1H--
tetrazol-5-ylmethoxy)-naphthalen-2-ylmethyl]-amide; or a
pharmaceutically acceptable salt or ester form thereof.
12. A compound of claim 1 which is selected from the group of:
2-Butyl-benzofuran-3-carboxylic acid
[5-(4-tert-butyl-phenyl)-6-(1H-tetra-
zol-5-ylmethoxy)-naphthalen-2-ylmethyl]-amide;
(6-{[(2-Butyl-benzofuran-3--
carbonyl)-amino]-methyl}-1-phenyl-naphthanen-2-yloxy)-acetic acid;
2-[6-{[(2-Butyl-benzofuran-3-carbonyl)-amino]-methyl}-1-(4-chloro-phenyl)-
-naphthalen-2-yloxy]-3-phenyl-propionic acid;
2-[6-{[(2-Butyl-benzofuran-3-
-carbonyl)-amino]-methyl}-1-(4-methoxy-phenyl)-naphthalen-2-yloxy]-3-pheny-
l-propionate; or 2-Butyl-benzofuran-3-carboxylic acid
[5-bromo-6-(1H-tetrazol-5-ylmethoxy)-naphthalen-2-ylmethyl]-methyl-amide;
or a pharmaceutically acceptable salt or ester form thereof.
13. A compound of claim 1 which is selected from the group of:
2-Ethyl-benzofuran-3-carboxylic acid
[5-bromo-6-(1H-tetrazol-5-ylmethoxy)-
-naphthalen-2-ylmethyl]-methyl-amide;
1-Phenyl-5-propyl-1H-pyrazole-4-carb- oxylic acid
[5-bromo-6-(1H-tetrazol-5-ylmethoxy)-naphthalen-2-ylmethyl]-me-
thyl-amide; 1-Benzyl-1H-indole-3-carboxylic acid
[5-bromo-6-(1H-tetrazol-5-
-ylmethoxy)-naphthalen-2-ylmethyl]-methyl-amide;
2-Butyl-benzofuran-3-carb- oxylic acid
methyl-[6-(1H-tetrazol-5-ylmethoxy)-naphthalen-2ylmethyl]-meth-
yl-amide; or 2-Butyl-1-methyl-1H-indole-3-carboxylic acid
[5-bromo-6-(1H-tetrazol-5-ylmethoxy)-naphthalen-2-ylmethyl]-methyl-amide;
or a pharmaceutically acceptable salt or ester form thereof.
14. A compound of claim 1 which is selected from the group of:
1-Methyl-1H-indole-3-carboxylic acid
[5-bromo-6-(1H-tetrazol-5-ylmethoxy)-
-naphthalen-2-ylmethyl]-methyl-amide;
5-(3,5-Dichloro-phenoxy)-furan-2-car- boxylic acid
[5-bromo-6-(1H-tetrazol-5-ylmethoxy)-naphthalen-2-ylmethyl]-m-
ethyl-amide; 3-Butyl-benzofuran-2-carboxylic acid
[5-bromo-6-(1H-tetrazol--
5-ylmethoxy)-naphthalen-2-ylmethyl]-methyl-amide;
2-Benzyl-3-(1-bromo-6-{[-
(3-butyl-benzofuran-2-carbonyl)-methyl-amino]-methyl}-naphthalen-2-yloxy)--
propionic acid; or 3-Methyl-benzofuran-2-carboxylic acid
[5-bromo-6-(1H-tetrazol-5-ylmethoxy)-naphthalen-2-ylmethyl]-methyl-amide;
or a pharmaceutically acceptable salt or ester form thereof.
15. A compound of claim 1 which is selected from the group of:
2-benzyl-3-(1-bromo-6-{[methyl-(3-methyl-benzofuran-2-carbonyl)-amino]-me-
thyl}-naphthalen-2-yloxy)-propionate;
3-Methyl-benzofuran-2-carboxylic acid
[5-bromo-6-(1H-tetrazol-5-ylmethoxy)-naphthalen-2-ylmethyl]-amide;
2-(1-Bromo-6-{[(3-methyl-benzofuran-2-carbonyl)-amino]-methyl}-naphthalen-
-2-yloxy)-3-phenyl-propionic acid;
3-Phenethyl-benzofuran-2-carboxylic acid
[5-bromo-6-(1H-tetrazol-5-ylmethoxy)-naphthalen-2-ylmethyl]-methyl-a-
mide; or
2-(1-Bromo-6-{[methyl-(3-phenethyl-benzofuran-2-carbonyl)-amino]--
methyl}-naphthalen-2-yloxy)-3-phenyl-propionic acid; or a
pharmaceutically acceptable salt or ester form thereof.
16. A compound of claim 1 which is selected from the group of:
(1-Bromo-6-{[methyl-(3-phenethyl-benzofuran-2-carbonyl)-amino]-methyl}-na-
phthalen-2-yloxy)-acetic acid; 2-Butyl-benzofuran-3-carboxylic acid
benzyl-[5-bromo-6-(1H-tetrazol-5-ylmethoxy)-naphthalen-2-ylmethyl]-amide;
2-Methyl-benzofuran-3-carboxylic acid
benzyl-[5-bromo-6-(1H-tetrazol-5-yl-
methoxy)-naphthalen-2-ylmethyl]-amide;
2-Ethyl-benzofuran-3-carboxylic acid
benzyl-[5-bromo-6-(1H-tetrazol-5ylmethoxy)-naphthalen-2-ylmethyl)-am-
ide; or 2-Butyl-benzofuran-3-carboxylic acid
[5-bromo-6-(1H-tetrazol-5-ylm-
ethoxy)-naphthalen-2-ylmethyl]-butyl-amide; or a pharmaceutically
acceptable salt or ester form thereof.
17. A compound of claim 1 which is selected from the group of:
2-Methyl-benzofuran-3-carboxylic acid
[5-bromo-6-(1H-tetrazol-5-ylmethoxy-
)-naphthalen-2-ylmethyl]-butyl-amide;
2-[1-Bromo-6-({[5-(3,5-dichloro-phen-
oxy)-furan-2-carbonyl]-amino}-methyl}-naphthalen-2-yloxy]-3-phenyl-propion-
ic acid;
2-(1-Bromo-6-{[(1-phenyl-5-propyl-1H-pyrazole-4-carbonyl)-amino]--
methyl}-naphthalen-2-yloxy)-3-phenyl-propionic acid;
2-{1-Bromo-6-[4-cyclohexyl-benzoylamino)-methyl]-naphthalen-2-yloxy}-3-ph-
enyl-propionic acid; or
2-{1-Bromo-6-[(3,5-di-tert-butyl-benzoylamino)-met-
hyl]-naphthalen-2-yloxy}-3-phenyl-propionic acid; or a
pharmaceutically acceptable salt or ester form thereof.
18. A compound of claim 1 which is selected from the group of:
2-{1-Bromo-6-[(3-phenoxy-benzoylamino)-methyl]-naphthalen-2-yloxy}-3-phen-
yl-propionic acid;
2-(1-Bromo-6-{[(2-ethyl-benzofuran-3-carbonyl)-amino]-m-
ethyl}-naphthalen-2-yloxy)-3-phenyl-propionic acid;
2-[1-Bromo-6-({[1-4-chloro-phenyl)-cyclopentanecarbonyl]-amino}-methyl)-n-
aphthalen-2-yloxy]-3-phenyl-propionic acid; or
2-Bromo-6-({[5-(3-trifluoro-
methyl-phenyl)-furan-2-carbonyl]-amino}-methyl)-naphthalen-2-yloxy]-3-phen-
yl-propionic acid; or a pharmaceutically acceptable salt or ester
form thereof.
19. A compound of claim 1 which is selected from the group of:
2-(1-Bromo-6-{[(4-cyclohexyl-benzoyl)-methyl-amino]-methyl}-naphthalen-2--
yloxy)-3-phenyl-propionic acid;
2-(1-Bromo-6-{[(2-butyl-benzofuran-3-carbo-
nyl)-methyl-amino]-methyl}naphthalen-2-yloxy)-3-phenyl-propionic
acid;
2-(1-Bromo-6-{[methyl-(4'-propyl-biphenyl-4-carbonyl)-amino]-methyl}-naph-
thalen-2-yloxy)-3-phenyl-propionic acid;
2-[1-Bromo-6-({[5-(3,5-dichloro-p-
henoxy)-furan-2-carbonyl]-methyl-amino}-methyl)-naphthalen-2-yloxy]-3-phen-
yl-propionic acid; or
2-(1-Bromo-6-{[(3,5-di-tert-butyl-benzoyl)-methyl-am-
ino]-methyl}-naphthalen-2-yloxy)-3-phenyl-propionic acid; or a
pharmaceutically acceptable salt or ester form thereof.
20. A compound of claim 1 which is selected from the group of:
2-(1-Bromo-6-{[methyl-(1-phenyl-5-propyl-1H-pyrazole-4-carbonyl)-amino]-m-
ethyl}-naphthalen-2-yloxy)-3-phenyl-propionic acid;
2-[6-({Benzyl-[5-(3,5-dichloro-phenoxy)-furan-2-carbonyl]-amino}-methyl)--
1-bromo-naphthalen-2-yloxy]-3-phenyl-propionic acid;
2-(6-{[Benzyl-(2-butyl-benzofuran-3-carbonyl)-amino]-methyl}-1-bromo-naph-
thalen-2-yloxy)-3-phenyl-propionic acid;
2-(6-{[Benzyl-(3,5-di-tert-butyl--
benzoyl)-amino]-methyl}-1-bromo-naphthalen-2-yloxy)-3-phenyl-propionic
acid; or
2-(6-{[Benzyl-(4'-propyl-biphenyl-4-carbonyl)-amino]-methyl}-1-b-
romo-naphthalen-2-yloxy)-3-phenyl propionic acid; or a
pharmaceutically acceptable salt or ester form thereof.
21. A compound of claim 1 which is selected from the group of:
2-(6-{[Benzyl-(4-cyclohexyl-benzoyl)-amino]-methyl}-1-bromo-naphthalen-2--
yloxy-3-phenyl-propionic acid;
2-(6-{[Benzyl-(1-phenyl-5-propyl-1H-pyrozol-
e-4-carbonyl)-amino]-methyl}-1-bromo-naphthalen-2-yloxy)-3-phenyl-propioni-
c acid;
(6-{[5-(2-Chloro-phenyl)-2-trifluoromethyl-furan-3-carbonyl]-amino-
}naphthalen-2-yloxy)-acetic acid;
(6-{[5-(3-Trifluoromethyl-phenyl)-furan--
2-carbonyl]-amino}-naphthalen-2-yloxy)-acetic acid; or
(6-{[1-(4-Chloro-phenyl)-cyclopentanecarbonyl]-amino}-naphthalen-2-yloxy)-
-acetic acid; or a pharmaceutically acceptable salt or ester form
thereof.
22. A compound of claim 1 which is selected from the group of:
[6-(2-Benzyloxy-benzoylamino)-naphthalen-2-yloxy]-acetic acid;
[6-(3,5-Di-tert-butyl-benzoylamino)-naphthalen-2yl oxy]-acetic
acid;
{6-[(5-Biphenyl-4-yl-2-trifluoromethyl-furan-3-carbonyl)-amino]-naphthale-
n-2-yloxy}-acetic acid;
(6-{[1-(4-Chloro-phenyl)-cyclohexanecarbonyl]-amin-
o}-naphathalen-2-yloxy)-acetic acid; or
(6-{[1-(4-Chloro-phenyl)-cyclobuta-
necarbonyl]-amino}-naphthalen-2-yloxy)-acetic acid; or a
pharmaceutically acceptable salt or ester form thereof.
23. A compound of claim 1 which is selected from the group of:
[6-({[5-(2-Chloro-phenyl)-2-trifluoromethyl-furan-3-carbonyl]-amino}-meth-
yl)-naphthalen-2-yloxy]-acetic acid;
[6-({[2-Trifluoromethyl-5-(4-trifluor-
omethyl-phenyl)-furan-3-carbonyl]-amino}methyl)-naphthalen-2-yloxy]-acetic
acid;
{6-[(2-Phenethyl-benzoylamino)-methyl]-naphthalen-2-yloxy}-acetic
acid;
[6-({[1-(4-Chloro-phenyl)-cyclopentanecarbonyl]-amino}-methyl)-naph-
thalen-2-yloxy]-acetic acid;
[6-({[5-(3-Trifluoromethyl-phenyl)-furan-2-ca-
rbonyl]-amino}-methyl)-naphthalen-2-yloxy]-acetic acid;
{6-[(3,5-Di-tert-butyl-benzoylamino)-methyl]-naphthalen-2-yloxy}-acetic
acid; or
(6-{[(1-Phenyl-cyclopentanecarbonyl)-amino]-methyl}-naphthalen-2-
-yloxy)-acetic acid; or a pharmaceutically acceptable salt or ester
form thereof.
24. A pharmaceutical composition comprising a pharmaceutically
effective amount of a compound of claim 1, or a pharmaceutically
acceptable salt or ester form thereof, a pharmaceutically
acceptable carrier or excipient.
25. A method of treatment of noninsulin dependent diabetes mellitus
in a mammal, the method comprising administering to a mammal in
need thereof a pharmaceutically effective amount of a compound of
claim 1, or a pharmaceutically acceptable salt or ester form
thereof.
26. A method of treatment or prevention of a prothrombotic or
thrombotic state or event in a mammal, the method comprising
administering to a mammal in need thereof a pharmaceutically
effective amount of a compound of claim 1, or a pharmaceutically
acceptable salt or ester form thereof.
27. A method of claim 26 wherein the prothrombotic or thrombotic
state or event is associated with coronary artery or
cerebrovascular disease.
28. A method of claim 26 wherein the prothrombotic or thrombotic
state or event is formation of atherosclerotic plaques, venous and
arterial thrombosis, myocardial ischemia, atrial fibrillation, deep
vein thrombosis, coagulation syndromes, pulmonary fibrosis,
cerebral thrombosis, thromboembolic complications of surgery or
peripheral arterial occlusion.
29. A method for the treatment of stroke associated with or
resulting from atrial fibrillation in a mammal, comprising
administering to a mammal in need thereof a pharmaceutically
effective amount of a compound of claim 1.
30. A method for the treatment of deep vein thrombosis in a mammal,
comprising administering to a mammal in need thereof a
pharmaceutically effective amount of a compound of claim 1.
31. A method for the treatment of myocardial ischemia in a mammal,
comprising administering to a mammal in need thereof a
pharmaceutically effective amount of a compound of claim 1.
32. A method for the treatment of cardiovascular disease caused by
noninsulin dependent diabetes mellitus in a mammal, comprising
administering to a mammal in need thereof a pharmaceutically
effective amount of a compound of claim 1.
33. A method for the treatment of the formation of atherosclerotic
plaques in a mammal, comprising administering to a mammal in need
thereof a pharmaceutically effective amount of a compound of claim
1.
34. A method for the treatment of chronic obstructive pulmonary
disease in a mammal, comprising administering to a mammal in need
thereof a pharmaceutically effective amount of a compound of claim
1.
35. A method for the treatment of renal fibrosis in a mammal,
comprising administering to a mammal in need thereof a
pharmaceutically effective amount of a compound of claim 1.
36. A method for the treatment of polycystic ovary syndrome in a
mammal, comprising administering to a mammal in need thereof a
pharmaceutically effective amount of a compound of claim 1.
37. A method for the treatment of Alzheimer's disease in a mammal,
comprising administering to a mammal in need thereof a
pharmaceutically effective amount of a compound of claim 1.
38. A method for the treatment of cancer in a mammal, comprising
administering to a mammal in need thereof a pharmaceutically
effective amount of a compound of claim 1.
Description
[0001] This invention relates to the composition and utility of
6-(aryl-amido or aryl-amidomethyl)-naphthalen-2-yloxy-acidic
derivatives as inhibitors of plasminogen activator inhibitor-1
(PAI-1) and as therapeutic compositions for treating conditions
resulting from fibrinolytic disorders such as deep vein thrombosis
and coronary heart disease, and pulmonary fibrosis.
BACKGROUND OF THE INVENTION
[0002] Plasminogen activator inhibitor-1 (PAI-1) is a major
regulatory component of the plasminogen-plasmin system. PAI-1 is
the principal physiologic inhibitor of both tissue type plasminogen
activator (tPA) and urokinase type plasminogen activator (uPA).
Elevated plasma levels of PAI-1 have been associated with
thrombotic events as indicated by animal experiments (Krishnamurti,
Blood, 69, 798 (1987); Reilly, Arteriosclerosis and Thrombosis, 11,
1276 (1991); Carmeliet, Journal of Clinical Investigation, 92, 2756
(1993)) and clinical studies (Rocha, Fibrinolysis, 8, 294,1994;
Aznar, Haemostasis 24, 243 (1994)). Antibody neutralization of
PAI-1 activity resulted in promotion of endogenous thrombolysis and
reperfusion (Biemond, Circulation, 91, 1175 (1995); Levi,
Circulation 85, 305, (1992)). Elevated levels of PAI-1 have also
been implicated in diseases of women such as polycystic ovary
syndrome (Nordt, Journal of clinical Endocrinology and Metabolism,
85, 4, 1563 (2000)) and bone loss induced by estrogen deficiency
(Daci, Journal of Bone and Mineral Research, 15, 8, 1510 (2000)).
Accordingly, agents that inhibit PAI-1 would be of utility in
treating conditions originating from fibrinolytic disorder such as
deep vein thrombosis, coronary heart disease, pulmonary embolism,
polycystic ovary syndrome, etc.
[0003] U.S. Pat. No. 5,530,019 describes compounds of the general
formula: 2
[0004] wherein R.sup.1 is optionally protected carboxy(lower)alkyl,
R.sup.2 is H, optionally substituted aryl or carboxy; X is a bond,
--O--, --NH-- or a cycloalkylene, and Y is an alkylene which may be
interrupted by an oxygen atom, an alkenylene or an alkadienylene,
which are described as useful as testosterone 5.alpha.-reductase
inhibitors useful in treating such diseases as prostatism,
prostatic hypertrophy, prostatic cancer, alopecia, hirsutism,
androgenic alopecia, acne, and other hyperandrogenisms.
DESCRIPTION OF THE INVENTION
[0005] This invention comprises compounds of the formula: 3
[0006] Wherein:
[0007] Ar is phenyl, naphthyl, furanyl, benzofuranyl, indolyl,
pyrazolyl, oxazolyl, fluorenyl, phenylcycloalkane where the
cycloalkane can be cyclopropyl, cyclobutyl, cyclopentyl or
cyclohexyl and Ar can be optionally substituted by from 1 to 3
groups selected from C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxy,
hydroxy, phenyl-(CH.sub.2).sub.0-6--, phenyl-(CH.sub.2).sub.0-6O--,
C.sub.3-C.sub.6 cycloalkyl, --(CH.sub.2)--C.sub.3-C.sub.6
cycloalkyl, halogen, C.sub.1-C.sub.3 perflouroalkyl and
C.sub.1-C.sub.3 perfluoroalkoxy where phenyl can be substituted
with from 1 to 3 groups selected from C.sub.1-C.sub.6 alkyl,
C.sub.1-C.sub.6 alkoxy, phenyl, halogen, trifluoromethyl or
trifluoromethoxy;
[0008] R.sub.1 is hydrogen, C.sub.1-C.sub.6 alkyl or
phenyl-(CH.sub.2).sub.1-6-- where phenyl can be substituted with
C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxy, halogen,
trifluoromethyl or trifluoromethoxy;
[0009] R.sub.2 and R.sub.3 are independently hydrogen,
C.sub.1-C.sub.6 alkyl, phenyl-(CH.sub.2).sub.0-3--, halogen and
C.sub.1-C.sub.3 perfluoroalkyl where phenyl can be substitute with
C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxy, halogen,
trifluoromethyl or trifluoromethoxy;
[0010] R.sub.4 is --CHR.sub.5CO.sub.2H, --CH.sub.2-tetrazole or an
acid mimic or mimetic; where R.sub.5 is hydrogen or optionally
substituted benzyl; and
[0011] n=0 or 1;
[0012] or a pharmaceutically acceptable salt or ester form
thereof.
[0013] One group of compounds of this invention includes those of
the formulae 1 or 4
[0014] R.sub.1 is hydrogen, C.sub.1-C.sub.6 alkyl or
phenyl-(CH.sub.2).sub.1-6-- where phenyl can be substituted with
C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxy, halogen,
trifluoromethyl or trifluoromethoxy.
[0015] R.sub.2 and R.sub.3 are independently hydrogen,
C.sub.1-C.sub.6 alkyl, phenyl-(CH.sub.2).sub.0-3--, halogen and
C.sub.1-C.sub.3 perfluoroalkyl where phenyl can be substitute with
C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxy, halogen,
trifluoromethyl or trifluoromethoxy.
[0016] R.sub.4 is --CHR.sub.5CO.sub.2H or an acid mimic such as
tetrazole, --CH.sub.2-tetrazole, SO.sub.3H, PO.sub.3H.sub.2,
tetronic acid, etc.;
[0017] R.sub.5 is hydrogen or benzyl;
[0018] R.sub.6 is selected from C.sub.1-C.sub.6 alkyl,
C.sub.1-C.sub.6 alkoxy, hydroxy, phenyl-(CH.sub.2).sub.0-6--,
phenyl-(CH.sub.2).sub.0-6O-- -, C.sub.3-C.sub.6, cycloalkyl,
halogen, C.sub.1-C.sub.3 perflouroalkyl and C.sub.1-C.sub.3
perfluoroalkoxy; where the phenyl ring in these R.sub.6 groups can
be substituted with C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxy,
phenyl-(CH.sub.2).sub.0-3--, halogen, trifluoromethyl or
trifluoromethoxy;
[0019] or a pharmaceutically acceptable salt or ester form
thereof.
[0020] A second group of compounds of this invention includes those
of the formula: 5
[0021] wherein:
[0022] Ar is a moiety selected from the group of: 6
[0023] R.sub.1 is hydrogen, C.sub.1-C.sub.6 alkyl or
phenyl-(CH.sub.2).sub.1-6-- where phenyl can be substituted with
C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxy, halogen,
trifluoromethyl or trifluoromethoxy.
[0024] R.sub.2 and R.sub.3 are independently hydrogen,
C.sub.1-C.sub.6 alkyl, phenyl-(CH.sub.2).sub.0-3--, halogen and
C.sub.1-C.sub.3 perfluoroalkyl where phenyl can be substitute with
C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxy, halogen,
trifluoromethyl or trifluoromethoxy.
[0025] R.sub.4 is --CHR.sub.5CO.sub.2H or an acid mimic such as
tetrazole, --CH.sub.2-tetrazole, SO.sub.3H, PO.sub.3H.sub.2,
tetronic acid, etc.;
[0026] R.sub.5 is hydrogen or benzyl;
[0027] R.sub.7 is selected from C.sub.1-C.sub.6 alkyl,
C.sub.1-C.sub.6 alkoxy, hydroxy, phenyl-(CH.sub.2).sub.0-6--,
phenyl-(CH.sub.2).sub.0-6O-- -, C.sub.3-C.sub.6 cycloalkyl,
halogen, C.sub.1-C.sub.3 perflouroalkyl and C.sub.1-C.sub.3
perfluoroalkoxy; where the phenyl ring in these R.sub.7 groups can
be substituted with C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6alkoxy,
phenyl, halogen, trifluoromethyl or trifluoromethoxy;
[0028] R.sub.8 and R.sub.9 are each independently selected from H,
C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxy,
phenyl-(CH.sub.2).sub.0-3-- -, halogen, trifluoromethyl or
trifluoromethoxy;
[0029] or a pharmaceutically acceptable salt or ester form
thereof.
[0030] A third subgroup of compounds of this invention comprises
those of the formula: 7
[0031] wherein:
[0032] R.sub.1 is hydrogen, C.sub.1-C.sub.6 alkyl or
phenyl-(CH.sub.2).sub.1-6-- where phenyl can be substituted with
C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxy, halogen,
trifluoromethyl or trifluoromethoxy.
[0033] R.sub.2 and R.sub.3 are independently hydrogen,
C.sub.1-C.sub.6 alkyl, phenyl-(CH.sub.2).sub.0-3--, halogen and
C.sub.1-C.sub.3 perfluoroalkyl where phenyl can be substitute with
C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxy, halogen,
trifluoromethyl or trifluoromethoxy.
[0034] R.sub.4 is --CHR.sub.5CO.sub.2H or an acid mimic such as
tetrazole, --CH.sub.2-tetrazole, SO.sub.3H, PO.sub.3H.sub.2,
tetronic acid, etc.;
[0035] R.sub.5 is hydrogen or benzyl;
[0036] R.sub.7 is selected from C.sub.1-C.sub.6 alkyl,
C.sub.1-C.sub.6 alkoxy, hydroxy, phenyl-(CH.sub.2).sub.0-6--,
phenyl-(CH.sub.2).sub.0-6O-- -, C.sub.3-C.sub.6, cycloalkyl,
halogen, C.sub.1-C.sub.3 perflouroalkyl and C.sub.1-C.sub.3
perfluoroalkoxy; where the phenyl ring in these R.sub.7 groups can
be substituted with C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxy,
phenyl-(CH.sub.2).sub.0-3--, halogen, trifluoromethyl or
trifluoromethoxy;
[0037] R.sub.8 and R.sub.9 are each independently selected from H,
C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxy, phenyl, halogen,
trifluoromethyl or trifluoromethoxy;
[0038] or a pharmaceutically acceptable salt or ester form
thereof.
[0039] A fourth subgroup of compounds of this invention comprises
those of the formula: 8
[0040] wherein:
[0041] R.sub.1 is hydrogen, C.sub.1-C.sub.6 alkyl or
phenyl-(CH.sub.2).sub.1-6-- where phenyl can be substituted with
C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxy, halogen,
trifluoromethyl or trifluoromethoxy.
[0042] R.sub.2 and R.sub.3 are independently hydrogen,
C.sub.1-C.sub.6 alkyl, phenyl-(CH.sub.2).sub.0-3--, halogen and
C.sub.1-C.sub.3 perfluoroalkyl where phenyl can be substitute with
C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxy, halogen,
trifluoromethyl or trifluoromethoxy.
[0043] R.sub.4 is --CHR.sub.5CO.sub.2H or an acid mimic such as
tetrazole, --CH.sub.2-tetrazole, SO.sub.3H, PO.sub.3H.sub.2,
tetronic acid, etc.;
[0044] R.sub.5 is hydrogen or benzyl;
[0045] R.sub.10 is selected from C.sub.1-C.sub.6 alkyl,
C.sub.1-C.sub.6 alkoxy, hydroxy, C.sub.3-C.sub.6, cycloalkyl,
halogen, C.sub.1-C.sub.3 perflouroalkyl and C.sub.1-C.sub.3
perfluoroalkoxy;
[0046] R.sub.11 is selected from C.sub.1-C.sub.6 alkyl,
phenyl-(CH.sub.2).sub.0-6--, C.sub.3-C.sub.6 cycloalkyl, or
--(CH.sub.2)-- C.sub.3-C.sub.6 cycloalkyl; where the phenyl ring in
these R.sub.7 groups can be substituted with C.sub.1-C.sub.6 alkyl,
C.sub.1-C.sub.6 alkoxy, phenyl, halogen, trifluoromethyl or
trifluoromethoxy;
[0047] Or a pharmaceutically acceptable salt or ester form
thereof.
[0048] A fifth subgroup of compounds of this invention are those of
the formula: 9
[0049] wherein:
[0050] R.sub.1 is hydrogen, C.sub.1-C.sub.6 alkyl or
phenyl-(CH.sub.2).sub.1-6-- where phenyl can be subsituted with
C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxy, halogen,
trifluoromethyl or trifluoromethoxy.
[0051] R.sub.2 and R.sub.3 are independently hydrogen,
C.sub.1-C.sub.6 alkyl, phenyl-(CH.sub.2).sub.0-3--, halogen and
C.sub.1-C.sub.3 perfluoroalkyl where phenyl can be substitute with
C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxy, halogen,
trifluoromethyl or trifluoromethoxy.
[0052] R.sub.4 is --CHR.sub.5CO.sub.2H or an acid mimic such as
tetrazole, --CH.sub.2-tetrazole, SO.sub.3H, PO.sub.3H.sub.2,
tetronic acid, etc.;
[0053] R.sub.5 is hydrogen or benzyl;
[0054] R.sub.8 and R.sub.9 are each independently selected from H,
C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxy, phenyl, halogen,
trifluoromethyl or trifluoromethoxy;
[0055] or a pharmaceutically acceptable salt or ester form
thereof.
[0056] The preferred salt forms of the compounds herein include but
are not limited to sodium salts, and potassium salts. Other useful
salt forms of these compounds include those formed with
pharmaceutically acceptable inorganic and organic bases known in
the art. Salt forms prepared using inorganic bases include
hydroxides, carbonates or bicarbonates of the therapeutically
acceptable alkali metals or alkaline earth methals, such as sodium
potassium, magnesium, calcium and the like. Acceptable organic
bases include amines, such as benzylzmine, mono-, di- and
trialkylamines, preferably those having alkyl groups of from 1 to 6
carbon atoms, more preferably 1 to 3 carbon atoms, such as
methylamine, dimethylamine, trimethylamine, ethylamine,
diethylamine, triethylamine, mono-, di-, and triethanolamine. Also
useful are alkylene diamines containing up to 6 carbon atoms, such
as hexamethylenediamine; cyclic saturated or unsaturated bases
containing up to 6 carbon atoms, including pyrrolidine, peperidine,
morpholine, piperazine and their N-alkyl and N-hydroxyalkyl
derivatives, such as N-methyl-morpholine and
N-(2-hyroxyethyl)-piperidine- , or pyridine. Quaternary salts may
also be formed, such as tetralkyl forms, such as tetramethyl forms,
alkyl-alkanol forms, such as methyl-triethanol or
trimethyl-monoethanol forms, and cyclic ammonium salt forms, such
as N-methylpyridinium, N-methyl-N-(2-hydroxyethyl)-morph- olinium,
N,N-di-methylmorpholinium, N-mehtyl-N-(2-hydroxyethyl)-morpholini-
um, or N,N-dimethyl-piperidinium salt forms. These salt forms may
be prepared using the acidic compound(s) of Formula I and
procedures known in the art.
[0057] Ester forms of the compounds of this invention include
straight chain alkyl esters having from 1 to 6 carbon atoms or
branched chain alkyl groups containing 3 or 6 carbon atoms,
including methyl, ethyl, propyl, butyl, 2-methylpropyl and
1,1-dimethylethyl esters. Other esters useful with this invention
include those of the formula --COOR.sub.5 wherein R.sub.5 is
selected from the formulae: 10
[0058] wherein R.sub.11, R.sub.12, R.sub.13, R.sub.14 are
independently selected from hydrogen, alkyl of from 1 to 10 carbon
atoms, aryl of 6 to 12 carbon atoms, arylalkyl of from 6 to 12
carbon atoms; heteroaryl or alkylheteroaryl wherein the heteroaryl
ring is bound by an alkyl chain of from 1 to 6 carbon atoms.
[0059] Among the preferred ester forms of the compounds herein
include but not limited to C.sub.1-C.sub.6 alkyl esters,
C.sub.3-C.sub.6 branched alkyl esters, benzyl esters, etc.
[0060] Acid mimic or mimetics which are included in the acidic
groups of this invention, as noted in the definition of A, above,
particularly include the pharmaceutically useful carboxylic acid
mimics or mimetics known in the art, such as those described in R.
Silverman, The Organic Chemistry of Drug Design and Drug Action,
Academic Press (1992), the contents of which are incorporated
herein by reference. Non-limiting examples of these acid mimics
include such as tetrazole, SO.sub.3H, PO.sub.3H.sub.2, tetronic
acid, etc., or groups having the formulae: 11
[0061] wherein R.sub.15 is C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6
alkenyl, C.sub.3-C.sub.6 cycloalkyl, --CH.sub.2--(C.sub.3-C.sub.6
cycloalkyl), C.sub.3-C.sub.6 cycloalkenyl,
--CH.sub.2--(C.sub.3-C.sub.6 cycloalkenyl), optionally substituted
aryl or heteroaryl groups or optionally substituted
--C.sub.1-C.sub.6 alkyl-aryl or --C.sub.1-C.sub.6 alkyl-heteroaryl,
with the aryl and heteroaryl groups and their optional substitution
as defined herein.
[0062] As used herein, "aryl" refers to an unsaturated aromatic
carbocyclic group of from 6 to 14 carbon atoms having a single ring
(e.g., phenyl) or multiple condensed (fused) rings (e.g., naphthyl
or anthryl). Preferred aryl groups include phenyl, naphthyl and the
like. As used herein, "heteroaryl" refers to a monocyclic or
bicyclic aromatic group of from 1 to carbon atoms and 1 to 4
heteroatoms selected from oxygen, nitrogen and sulfur within at
least one ring (if there is more than one ring). Such heteroaryl
groups can have a single ring, such as pyridyl, pyrrolyl or furyl
groups, or multiple condensed rings, such as indolyl, indolizinyl,
benzofuranyl or benzothienyl groups. Preferred heteroaryls include
pyridyl, pyrrolyl and furyl.
[0063] Unless otherwise limited by the definition for the aryl or
heteroaryl groups herein, such groups can optionally be substituted
with from 1 to 5 substituents selected from the group consisting of
acyloxy, hydroxy, acyl, alkyl of 1 to 6 carbon atoms, alkoxy of 1
to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms, alkynyl of 2 to
6 carbon atoms, substituted alkyl, substituted alkoxy, substituted
alkenyl, substituted alkynyl, amino, amino substituted by one or
two alkyl groups of from 1 to 6 carbon atoms, aminoacyl, acylamino,
azido, cyano, halo, nitro, thioalkoxy of from 1 to 6 carbon atoms,
substituted thioalkoxy of from 1 to 6 carbon atoms, and
trihalomethyl. Substituents on the alkyl, alkenyl, alkynyl,
thioalkoxy and alkoxy groups mentioned above include halogens, CN,
OH, and amino groups. Preferred substituents on the aryl groups
herein include alkyl, alkoxy, halo, cyano, nitro, trihalomethyl,
and thioalkoxy.
[0064] The compounds of the present invention are inhibitors of the
serine protease inhibitor PAI-1, and are therefore useful in the
treatment, inhibition, prevention or prophylaxis in a mammal,
preferably in a human, of those processes which involve the
production and/or action of PAI-1. Thus, the compounds of the
invention are useful in the treatment or prevention of noninsulin
dependent diabetes mellitus and cardiovascular disease caused by
such condition, and prevention of thrombotic events associated with
coronary artery and cerebrovascular disease. These compounds are
also useful for inhibiting the disease process involving the
thrombotic and prothrombotic states which include, but are not
limited to, formation of atherosclerotic plaques, venous and
arterial thrombosis, myocardial ischemia, atrial fibrillation, deep
vein thrombosis, coagulation syndromes, pulmonary fibrosis,
cerebral thrombosis, thromboembolic complications of surgery (such
as joint replacement), and peripheral arterial occlusion. These
compounds are also useful in treating stroke associated with or
resulting from atrial fibrillation.
[0065] The compounds of the invention may also be used in the
treatment of diseases associated with extracellular matrix
accumulation, including, but not limited to, renal fibrosis,
chronic obstructive pulmonary disease, polycystic ovary syndrome,
restenosis, renovascular disease and organ transplant
rejection.
[0066] The compounds of the invention may also be used in the
treatment of malignancies, and diseases associated with
neoangiogenesis (such as diabetic retinopathy).
[0067] The compounds in the invention may also be used in
conjunction with and following processes or procedures involving
maintaining blood vessel patency, including vascular surgery,
vascular graft and stent patency, organ, tissue and cell
implantation and transplantation.
[0068] The compounds in the invention may also be useful in the
treatment of inflammatory diseases, septic shock and the vascular
damage associated with infections.
[0069] The compounds of the invention are useful for the treatment
of blood and blood products used in dialysis, blood storage in the
fluid phase, especially ex vivo platelet aggregation. The present
compounds may also be added to human plasma during the analysis of
blood chemistry in hospital settings to determine the fibrinolytic
capacity thereof.
[0070] The compounds in the present invention may also be used in
combination with prothrombolytic, fibrinolytic and anticoagulant
agents.
[0071] The compounds of the present invention may also be used to
treat cancer including, but not limited to, breast and ovarian
cancer, and as imaging agents for the identification of metastatic
cancers.
[0072] The compounds of the invention may also be used in the
treatment of Alzheimer's disease. This method may also be
characterized as the inhibition of plasminogen activator by PAI-1
in a mammal, particularly a human, experiencing or subject to
Alzhemier's disease. This method may also be characterized as a
method of increasing or normalizing levels of plasmin concentration
in a mammal, particularly those experiencing or subject to
Alzheimer's disease.
[0073] The compounds of the invention may be used for the treatment
of myelofibrosis with myeloid metaplasia by regulating stromal cell
hyperplasia and increases in extracellular matrix proteins.
[0074] The compounds of the invention may also be used in
conjunction with protease inhibitor-containing highly active
antiretroviral therapy (HAART) for the treatment of diseases which
orginate from fibrinolytic impairment and hyper-coagulability of
HIV-1 infected patients receiving such therapy.
[0075] The compounds of the invention may be used for the treatment
of diabetic nephropathy and renal dialysis associated with
nephropathy.
[0076] The compounds of the invention may be used to treat cancer,
septicemia, obesity, insulin resistance, proliferative diseases
such as psoriasis, improving coagulation homeostasis,
cerebrovascular diseases, microvascular disease, hypertension,
dementia, osteoporosis, arthritis, asthma, heart failure,
arrhythmia, angina, and as a hormone replacement agent, treating,
preventing or reversing progression of atherosclerosis, Alzheimer's
disease, osteoporosis, osteopenia; reducing inflammatory markers,
reducing C-reactive protein, or preventing or treating low grade
vascular inflammation, stroke, dementia, coronary heart disease,
primary and secondary prevention of myocardial infarction, stable
and unstable angina, primary prevention of coronary events,
secondary prevention of cardiovascular events, peripheral vascular
disease, peripheral arterial disease, acute vascular syndromes,
reducing the risk of undergoing a myocardial revascularization
procedure, microvascular diseases such as nephropathy, neuropathy,
retinopathy and nephrotic syndrome, hypertension, Type I and 2
diabetes and related diseases, hyperglycemia, hyperinsulinemia,
malignant lesions, premalignant lesions, gastrointestinal
malignancies, liposarcomas and epithelial tumors, proliferative
diseases such as psoriasis, improving coagulation homeostasis,
and/or improving endothelial function, and all forms of
cerebrovascular diseases.
[0077] The compounds of the invention may be used for the topical
applications in wound healing for prevention of scarring.
[0078] Methods for the treatment, inhibition, prevention or
prophylaxis in a mammal of each of the conditions or maladies
listed herein are part of the present invention. Each method
comprises administering to a mammal in need thereof a
pharmaceutically or therapeutically effective amount of a compound
of this invention, or a pharmaceutically acceptable salt or ester
form thereof.
[0079] This invention also provides pharmaceutical compositions
comprising a pharmaceutically or therapeutically effective amount
of a compound of this invention, or a pharmaceutically acceptable
salt or ester form thereof, either alone or in combination with one
or more pharmaceutically acceptable carriers or excipients (i.e.
pharmaceutically acceptable materials with no pharmacological
effects). It will be understood that a pharmaceutically or
therapeutically effective amount of a compound herein refers to an
amount of the compound in question which will sufficiently inhibit
the serine protease inhibitor PAI-1 in the mammal in need thereof
to a sufficient extent to provide a desirable improvement in the
condition in question or provide sufficient inhibition of the
serine protease inhibitor PAI-1 to prevent, inhibit or limit the
onset of the physiological basis for the malady or condition in
question.
DETAILED DESCRIPTION OF THE INVENTION
[0080] The compounds of this invention are conveniently prepared by
the routes shown in Scheme 1, 2 and 3. Specific examples are given
in the Experimental Section. These examples are for illustrative
purposes only and are not to be construed as limiting to this
disclosure in any way. Those skilled in the art will be aware of
other methods of preparing the compounds of this invention. The
starting materials are available commercially or can be prepared by
standard literature procedures. 12 13 14
[0081] This invention also provides pharmaceutical compositions
comprised of 6-(aryl-amido or
aryl-amidomethyl)-naphthalen-2-yloxy-acidic derivatives either
alone or in combination with excipients (i.e. pharmaceutically
acceptable materials with no pharmacological effects). Such
compositions for treating conditions resulting from fibrinolytic
disorder such as deep vein thrombosis and coronary heart disease,
pulmonary fibrosis, etc.
[0082] The precise dosage to be employed depends upon several
factors including the host, whether in veterinary medicine or human
medicine, the nature and severity of the condition being treated,
the mode of administration and the particular active substance
employed. The compounds may be administered by any conventional
route, in particular enterally, preferably orally in the form of
tablets or capsules. Administered compounds can be in the free form
or pharmaceutically acceptable salt form as appropriate, for use as
a pharmaceutical, particularly for use in the prophylactic or
curative treatment of atherosclerosis and sequelae (angina
pectoris, myocardial infarction, arrhythmias, heart failure, kidney
failure, stroke, peripheral arterial occlusion, and related disease
states). These measures will slow the rate of progress of the
disease state and assist the body in reversing the process
direction in a natural manner.
[0083] Any suitable carrier known to the art can be used to prepare
the pharmaceutical compositions. In such a composition, the carrier
may be a solid, liquid or mixture of a solid and a liquid. Solid
compositions include powders, tablets and capsules. A solid carrier
can be one or more substances which may also act as a flavoring
agent, lubricant, solubilizer, suspending agent, binder, or tablet
disintegrant. In powders, the carrier is a finely divided solid,
which is in admixture with the finely divided active ingredient. In
tablets, the active ingredient is mixed with a carrier having the
necessary binding properties in suitable proportions and compacted
in the shape and size desired. Suitable solid carriers are
magnesium carbonate, magnesium stearate, talc, sugar, lactose,
pectin, dextrin, starch, gelatin, tragacanth, methyl cellulose,
hydroxymethyl cellulose, sodium carboxymethyl cellulose, a low
melting wax, cocoa butter, and the like. Encapsulating materials
may also be employed with the compounds of this invention, and the
term "composition" is intended to include the active ingredient in
combination with an encapsulating material as a formulation, with
or without other carriers. Cachets may also be used in the delivery
of the anti-atherosclerotic medicament of this invention.
[0084] Sterile liquid compositions include solutions, suspensions,
emulsions, syrups and elixirs. The compounds of this invention may
be dissolved or suspended in the pharmaceutically acceptable
carrier, such as sterile water, sterile organic solvent or a
mixture of both. Preferably the liquid carrier is one suitable for
parental injection. Where the compounds are sufficiently soluble
they can be dissolved directly in normal saline with or without the
use of suitable organic solvents, such as propylene glycol or
polyethylene glycol. If desired, dispersions of the finely divided
compounds can be made-up in aqueous starch or sodium carboxymethyl
cellulose solution, or in a suitable oil, such as arachis oil.
Liquid pharmaceutical compositions, which are sterile solutions or
suspensions, can be utilized by intramuscular, intraperitoneal or
subcutaneous injection. In many instances a liquid composition form
may be used instead of the preferred solid oral method of
administration.
[0085] It is preferred to prepare unit dosage forms of the
compounds for standard administration regimens. In this way, the
composition can be subdivided readily into smaller doses at the
physicians direction. For example, unit dosages may be made up in
packeted powders, vials or ampoules and preferably in capsule or
tablet form. The active compound present in these unit dosage forms
of the composition may be present in an amount of from about one
gram to about fifteen grams or more, for single or multiple daily
administration, according to the particular need of the patient.
The daily dose of active compound will vary depending upon the
route of administration, the size, age and sex of the patient, the
severity of the disease state, and the response to the therapy as
traced by blood analysis and the patients recovery rate. By
initiating the treatment regimen with a minimal daily dose of about
one gram, the blood levels of PAI-1 and the patients symptomatic
relief analysis may be used to determine whether a larger dose is
indicated. Based upon the data presented below, the projected daily
dose for both human and veterinary use will be from about 25 to
about 200 milligrams/kilogram per day, and more usually, from about
50 to about 100 milligrams/kilogram per day.
[0086] The ability of the compounds of this invention to inhibit
Plasminogen Activator Inhobitor (type I) was established by the
following experimental procedures:
[0087] Primary Screen for the PAI-1 Inhibition
[0088] Test compounds are dissolved in DMSO at a final
concentration of 10 mM, then diluted 100.times.in physiologic
buffer. The inhibitory assay is initiated by the addition of the
test compound (1-100 .mu.M final concentration, maximum DMSO
concentration of 0.2%) in a pH 6.6 buffer containing 140 nM
recombinant human plasminogen activator inhibitor-1 (PAI-1;
Molecular Innovations, Royal Oak, Mich.). Following a 1 hour
incubation at room temperature, 70 nM of recombinant human tissue
plasminogen activator (tPA) is added, and the combination of the
test compound, PAI-1 and tPA is incubated for an additional 30
minutes. Following the second incubation, Spectrozyme-tPA (American
Diagnostica, Greenwich, Conn.), a chromogenic substrate for tPA, is
added and absorbance read at 405 nm at 0 and 60 minutes. Relative
PAI-1 inhibition is equal to the residual tPA activity in the
presence of the test compound and PAI-1. Control treatments include
the complete inhibition of tPA by PAI-1 at the molar ratio employed
(2:1), and the absence of any effect of the test compound on tPA
alone.
[0089] Assay for Determining IC.sub.50 of Inhibition of PAI-1
[0090] This assay is based upon the non-SDS dissociable interaction
between tPA and active PAI-1. Assay plates are initially coated
with human tPA (10 .mu.g/ml). The test compounds are dissolved in
DMSO at 10 mM, then diluted with physiologic buffer (pH 7.5) to a
final concentration of 1-50 .mu.M. The test compounds are incubated
with human PAI-1 (50 ng/ml) for 15 minutes at room temperature. The
tPA-coated plate is washed with a solution of 0.05% Tween 20 and
0.1% BSA, then the plate is blocked with a solution of 3% BSA. An
aliquot of the test compound/PAI-1 solution is then added to the
tPA-coated plate, incubated at room temperature for 1 hour, and
washed. Active PAI-1 bound to the plate is assessed by adding an
aliquot of a 1:1000 dilution of the 33B8 monoclonal antibody
against human PAI-1, and incubating the plate at room temperature
for 1 hour (Molecular Innovations, Royal Oak, Mich. The plate is
again washed, and a solution of goat anti-mouse IgG-alkaline
phosphatase conjugate is added at a 1:50,000 dilution in goat
serum. The plate is incubated 30 minutes at room temperature,
washed, and a solution of alkaline phosphatase substrate is added.
The plate is incubated 45 minutes at room temperature, and color
development is determined at OD.sub.405nm. The quantitation of
active PAI-1 bound to tPA at varying concentrations of the test
compound is used to determine the IC.sub.50. Results are analyzed
using a logarithmic best-fit equation. The assay sensitivity is 5
ng/ml of human PAI-1 as determined from a standard curve ranging
from 0-100 ng/ml.
[0091] The compounds of the present invention inhibited Plasminogen
Activator Inhibitor-1 as summarized in Table I:
1 TABLE I % Inhib. Example IC.sub.50 (.mu.M).sup.a IC.sub.50
(.mu.M).sup.b 100 .mu.M 25 .mu.M 1 23 2 52 21 3 3.2 75 38 4 66 3 5
47 6 18.3 67 43 7 16.62 7.8 83 64 8 22.9 71 13 9 89 28 10 25.2 53 7
11 32 12 66 5 13 52 5 14 51 70 1 15 92 5 16 85 12 17 16.11 1.4 80
18 15.72 92 53 19 32 20 15.8 58 26 21 5.08 54 36 22 70 12 23 48 24
16.82 9.94 72 25 25 4.6 94 3 26 4.3 98 20 27 39 28 20.2 100 22 29
8.5 100 23 30 44.94 91 38 31 8.47 15.6 95 62 32 25.88 70 1 33 31.13
94 59 34 19.3 81 34 35 72 26 36 46 4 37 20.64 96 52 38 81 47 39 69
24 40 96 60 41 91 49 42 79 63 43 71 47 44 45 17 46 88 58 47 90 59
48 17.51 20.9 85 48 49 6.92 72 54 50 35.66 61 56 51 18.67 6.9 91 69
52 20.78 81 44 53 8.12 8.7 86 35 54 11.8 80 18 55 16.8 11.8 60 35
56 1.9 100 84 57 5.5 98 24 58 29 59 44 60 30 61 75 24 62 84 1 63 69
14 64 13.61 60 40 65 14.64 88 46 66 95 46 67 13.47 66 59 68 19.96
84 54 69 16.78 92 55 70 81 17 71 78 47 72 68 56 73 65 23 74 59 20
75 55 1 76 54 0 77 51 27 78 51 24 79 50 19 80 48 81 36.5 78 12 82
68 9 83 45 84 34 85 34 86 33 87 32 .sup.aThe IC.sub.50 was
determined by the Antibody Assay described above. .sup.bThe
IC.sub.50 was deteremined by a modification of the Primary Screen
for the PAI-1 Inhibition.
[0092] This invention is further illustrated by the following
non-limiting examples.
EXAMPLE 1
(6-{[Benzofuran-2-carbonyl)-amino]-methyl}-naphthalen-2-yloxy)-acetic
acid
[0093] Step 1: C-(6-Methoxy-naphthalen-2-yl)-methylamine.
BH.sub.3-THF (245 mL of a 1 M solution, 245 mmol) was added under
nitrogen dropwise over 30 minutes to a solution of
6-methoxy-naphthalene-2-carbonitrile (15.0 g, 82 mmol) in 300 mL of
anhydrous THF at room temperature. After the addition the reaction
was refluxed for 22 h. By TLC starting material remained. An
additional 82 mL (82 mmol) of BH.sub.3-THF was added and the
reaction refluxed for 3 h. 1 N HCL was added slowly until the
reaction was acidic. The reaction was concentrated under reduced
pressure to remove the THF. The solid present was removed by
filtration and the filtrate made basic by the addition of 5%
NaHCO.sub.3. The solid which precipitated was collected by
filtration and dried under reduced pressure to give
C(6-Methoxy-naphthalen-2-yl)-methylamine (11.35 g, 74%) as a white
solid, mp 115-122.degree. C., MS m/z 187 [M].sup.+.
[0094] Elemental Analysis for C.sub.12H.sub.13NO+0.66 H.sub.2O
Calc'd: C, 72.38; H, 7.25; N, 7.03 Found: C, 65.88; H, 6.57; N,
5.86
[0095] Step 2: 6-Hydroxy-naphthalen-2-ylmethyl-ammonium; bromide. A
mixture of C(6-methoxy-naphthalen-2-yl)-methylamine (13.0 g, 69
mmol), prepared in the previous step, and 350 mL of 48% HBr was
refluxed for 24 h. The solvent was removed under reduced pressure
to give 6-hydroxy-naphthalen-2-ylmethyl-ammonium; bromide (18.5 g,
95%) as a brown solid, MS m/z 173 [M].sup.+.
[0096] Elemental Analysis for C.sub.11H.sub.12BrNO+1.55 H.sub.2O
Calc'd: C, 46.48; H, 5.40; N, 4.97 Found: C, 42.96; H, 4.31; N,
4.50
[0097] Step 3: Benzofuran-2-carbonyl chloride. DMF (75 .mu.L) was
added under nitrogen to a solution of benzofuran-2-carboxylic acid
(5.0 g, 30.8 mmol) and oxalyl chloride (13.3 mL, 154 mmol) in 175
mL of methylene chloride at room temperature. After the addition
the reaction was stirred at room temperature for 1 h. The solvent
and excess oxalyl chloride were removed under reduced pressure to
give 5.72 g of a white solid which was used in the next step
without additional purification.
[0098] Step 4: Benzofuran-2-carboxylic acid
(6-hydroxy-naphthalen-2-ylmeth- yl)-amide. Benzofuran-2-carbonyl
chloride (5.02 g, 27.8 mmol), prepared in the previous step, in 100
mL of anhydrous THF was added under nitrogen dropwise over 30
minutes to a mixture of 6-hydroxy-naphthalen-2-ylmethyl-- ammonium;
bromide (7.06 g, 27.8 mmol), prepared in step 2, and triethylamine
(8.5 mL, 61.1 mmol) in 400 mL of anhydrous THF at ice bath
temperature. After the addition the reaction was stirred at ice
bath temperature for approximately 2 h and then overnight at room
temperature. The solid was removed by filtration and the filtrate
concentrated under reduced pressure to give 9.14 g a brown foam. To
remove residual amounts of triethylamine the foam was triturated
with water. Methylene chloride (150 mL) was added to the residue.
The material that did not dissolve was collected by filtration and
dried under reduced pressure to give benzofuran-2-carboxylic acid
(6-hydroxy-naphthalen-2-ylmethyl)-amide (1.44 g, 15%) as a brown
solid. Upon cooling the filtrate a solid formed. The solid was
collected by filtration and dried under reduced pressure to give an
additional 2.46 g (26%) of the desired product, mp 200-202.degree.
C.
[0099] Elemental Analysis for C.sub.20H.sub.15NO.sub.3+0.23
CH.sub.2Cl.sub.2 Calc'd: C, 72.13; H, 4.63; N, 4.16 Found: C,
69.30; H, 4.58; N, 3.93
[0100] Step 5:
(6-{[Benzofuran-2-carbonyl)-amino]-methyl}-naphthalen-2-ylo-
xy)-acetic acid methyl ester. A mixture of benzofuran-2-carboxylic
acid (6-hydroxy-naphthalen-2-ylmethyl)-amide (1.5 g, 4.73 mmol),
prepared in the previous step, methyl bromoacetate (473 .mu.L,
mmol) and potassium carbonate (3.27 g, 23.6 mmol) in 30 mL of DMF
was stirred under nitrogen at room temperature overnight. The
reaction was diluted with methylene chloride, extracted multiple
times with water, dried (MgSO.sub.4) and the solvent removed under
reduced pressure to give 1.66 g of a tan solid. Recrystallization
of the solid from isopropyl alcohol gave
(6-{[benzofuran-2-carbonyl)-amino]-methyl}-naphthalen-2-yloxy)-acetic
acid methyl ester (1.12 g, 60%) as a tan solid, mp 170-171.degree.
C.
[0101] Elemental Analysis for C.sub.23H.sub.19NO.sub.5 Calc'd: C,
70.94; H, 4.92; N, 3.60 Found: C, 70.01; H, 5.23; N, 3.47
[0102] Step 6:
(6-{[Benzofuran-2-carbonyl)-amino]-methyl}-naphthalen-2-ylo-
xy)-acetic acid. A mixture of
(6-{[benzofuran-2-carbonyl)-amino]-methyl}-n-
aphthalen-2-yloxy)-acetic acid methyl ester (947 mg, 2.43 mmol),
prepared in the previous step, and 1 N NaOH (2.7 mL, 2.67 mmol) in
50 mL of THF and 25 mL of water was stirred at room temperature for
2 h. The reaction was concentrated under reduced pressure to remove
the THF. A white solid was present in the residual aqueous layer.
This aqueous mixture was diluted with 250 mL of boiling water. The
solid that did not dissolve was collected by filtration and dried
under reduced pressure to give
(6-{[benzofuran-2-carbonyl)-amino]-methyl}-naphthalen-2-yloxy)-acetic
acid as its sodium salt (303 mg, 27%) as a light pink solid. When
the filtrate cooled to room temperature additional solid formed.
The solid was collected by filtration and dried under reduced
pressure to give an additional 328 mg (29%) of the salt. The
filtrate was then acidified with 1 N HCl. A solid immediately
precipitated. The solid was collected by filtration and dried under
reduced pressure to give the title compound (40 mg, 4%) as a brown
solid, mp 143-147.degree. C.; MS m/z 374 [M-H].sup.-.
[0103] Elemental Analysis for C.sub.22H.sub.17NO.sub.5 Calc'd: C,
70.39; H, 4.56; N, 3.73 Found: C, 66.37; H, 4.75; N, 3.52
EXAMPLE 2
Benzofuran-2-carboxylic acid
[6-(2H-tetrazol-5-ylmethoxy-naphthalen-2-ylme- thyl]-amide
[0104] Step 1: Benzofuran-2-carboxylic acid
(6-cyanomethoxy-naphthalen-2-y- lmethyl)-amide. A mixture of
benzofuran-2-carboxylic acid
(6-hydroxy-naphthalen-2-ylmethyl)-amide (1.35 g, 4.27 mmol),
prepared in step 4 of Example 1, bromoacetonitrile (326 .mu.L, 4.69
mmol) and potassium carbonate (2.9 g, 21.3 mmol) in 25 mL of DMF
was stirred under nitrogen at room temperature overnight. By TLC
starting material remained. An additional 594 .mu.L (8.53 mmol) of
bromoacetonitrile was added and the reaction stirred at room
temperature overnight. The reaction was diluted with methylene
chloride, extracted multiple times with water, dried (MgSO.sub.4)
and the solvent removed under reduced pressure to give 1.27 g of a
brown solid. Purification of the solid on a 90 g KP-SIL 60 A.sup.0
Biotage column using 1% ethyl acetate in methylene chloride as the
eluent gave benzofuran-2-carboxylic acid
(6-cyanomethoxy-naphthalen-2-ylmethyl)-amide (420 mg, 28%) as a
white solid, mp 138-139.degree. C.
[0105] Elemental Analysis for C.sub.22H.sub.16N.sub.2O.sub.3
Calc'd: C, 74.15; H, 4.53; N, 7.86 Found: C, 72.71; H, 4.28; N,
7.62
[0106] Step 2: Benzofuran-2-carboxylic acid
[6-(2H-tetrazol-5-ylmethoxy-na- phthalen-2-ylmethyl]-amide. A
mixture of benzofuran-2-carboxylic acid
(6-cyanomethoxy-naphthalen-2-ylmethyl)-amide (200 mg, 0.561 mmol),
prepared in the previous step, sodium azide (109 mg, 1.68 mmol) and
ammoniun chloride (90 mg, 1.68 mmol) in 10 mL of DMF was stirred
under nitrogen at 100.degree. C. for 4 h. The reaction was diluted
with water, made basic by the addition of 1 N NaOH and extracted
three times with methylene chloride. The solid present in the
aqueous layer was collected by filtration and dried to give 143 mg
of material. The solid was taken up in 150 mL of boiling water and
filtered. While warm the filtrate was acidified by the addition of
1 N HCl. The solid that formed was collected by filtration and
dried under reduced pressure to give the title compound (110 mg,
49%) as a white solid, mp 212-213.degree. C.
[0107] Elemental Analysis for C.sub.22H.sub.17N.sub.5O.sub.3+0.40
H.sub.2O Calc'd: C, 64.99; H, 4.41; N, 17.22 Found: C, 64.40; H,
4.21; N, 17.24
EXAMPLE 3
2-Butyl-benzofuran-3-carboxylic acid
[6-(2H-tetrazol-5-ylmethoxy)-naphthal- en-2-yl]-amide
[0108] Step 1: 2-Butyl-benzofuran-3-carboxylic acid. Oxalyl
chloride (9.9 mL, 113 mmol) in 50 mL of anhydrous carbon disulfide
was added under nitrogen at room temperature to a suspension of
aluminum chloride (18.2 g, 136 mmol) in 400 mL of anhydrous carbon
disulfide. After the addition the reaction was stirred at room
temperature for 15 minutes. 2-Butyl-benzofuran (20.0 mL, 113 mmol)
in 50 mL of anhydrous carbon disulfide was then added dropwise over
30 minutes. After the addition the reaction was refluxed for 2 h.
After cooling to room temperature 50 mL of 1 N HCl was added
dropwise to the reaction (exotherm). The carbon disulfide was
decanted from a purple sludge. The sludge was extracted with
methylene chloride, combined with the carbon disulfide solution and
the solvent removed under reduced pressure. The residue was
partitioned between methylene chloride and water. The organic layer
was separated and the aqueous layer extracted two times with
methylene chloride. The combined extracts were dried (MgSO.sub.4)
and the solvent removed under reduced pressure. The residue was
dissolved in 300 mL of THF plus 300 mL of 1 N NaOH and the mixture
stirred at room temperature for 16 h (overnight). The THF was
removed under reduced pressure and the residue partitioned between
methylene chloride and water. The emulsion that formed was
separated by the addition of saturated NaCl. After separating the
organic layer the aqueous layer was extracted two times with
methylene chloride. The aqueous layer was filtered to remove some
suspended solid and then partitioned with 10%
MeOH--CH.sub.2Cl.sub.2 and acidified with 1 N HCl. The organic
layer was separated and the aqueous layer extracted two times with
10% MeOH--CH.sub.2Cl.sub.2. The combined extracts were dried
(MgSO.sub.4) and the solvent removed under reduced pressure to give
2-butyl-benzofuran-3-carboxylic acid (11.50 g, 47%) as a dark
yellow solid, mp 106-110.degree. C.
[0109] Elemental Analysis for C.sub.13H.sub.14O.sub.3 Calc'd: C,
71.54; H, 6.47; N, 0.00 Found: C, 70.79; H, 6.45; N, 0.01
[0110] Step 2: 2-Butyl-benzofuran-3-carbonyl chloride. Oxalyl
Chloride (10.0 mL, 114.6 mmol) was added under nitrogen at room
temperature to a solution of 2-butyl-benzofuran-3-carboxylic acid
(5.00 g, 22.9 mmol), prepared in the previous step, in 200 mL of
methylene chloride. After the addition a catalytic amount of DMF
(100 .mu.L) was added and the reaction stirred at room temperature
for 1.5 h. The solvent was removed under reduced pressure to give a
brown oil. The oil was dissolved in benzene and the solvent removed
under reduced pressure to give 2-butyl-benzofuran-3-carbonyl
chloride (5.46 g, 100%) as a brown oil. The material was
immediately used in subsequent reactions with out additional
purification.
[0111] Step 3: (6-Methoxy-naphthalen-2-yl)-carbamic acid tert-butyl
ester. A mixture of 6-methoxy-naphthalene-2-carboxylic acid (10.00
g, 49.5 mmol), triethylamine (6.9 mL, 49.5 mmol) and
diphenylphosphoryl azide (10.7 mL, 49.6 mmol) in 200 mL of
anhydrous tert-butyl alcohol was refluxed under nitrogen for 5.5 h.
The tert-butyl alcohol was removed under reduced pressure. The
residue was dissolved in methylene chloride and extracted with 1 N
HCl, 1 N NaOH, dried (MgSO.sub.4) and the solvent removed under
reduced pressure to give (6-Methoxy-naphthalen-2-yl)-carbam- ic
acid tert-butyl ester (11.14 g, 82%) as an off-white solid, mp
124-127.degree. C.
[0112] Elemental Analysis for C.sub.16H.sub.19NO.sub.3 Calc'd: C,
70.31; H, 7.01; N, 5.12 Found: C, 69.83; H, 7.01; N, 5.24
[0113] Step 4: 6-Amino-naphthalen-2-ol.
(6-Methoxy-naphthalen-2-yl)-carbam- ic acid tert-butyl ester (10.05
g, 36.8 mmol), prepared in the previous step, was suspended in 300
mL of glacial acetic acid plus 200 mL of 48% HBr and under nitrogen
the mixture was refluxed for 6 h. The glacial acetic acid and the
48% HBr were removed under reduced pressure and the residue
partitioned between methylene chloride and water. The aqueous layer
was made basic by the addition of NaHCO.sub.3. A solid
precipitated. The solid was collected by filtration and dried under
reduced pressure to give 6-amino-naphthalen-2-ol (5.72 g, 98%) as a
gray solid, MS m/z: 160 [M+H].sup.+.
[0114] Elemental Analysis for C.sub.10H.sub.9NO Calc'd: C, 75.45;
H, 5.70; N, 8.80 Found: C, 65.71; H, 4.70; N, 7.40
[0115] Step 5: 2-Butyl-benzofuran-3-carboxylic acid
(6-hydroxy-naphthalen-2-yl)-amide. 2-Butyl-benzofuran-3-carbonyl
chloride, prepared in step 2, in 100 mL of anhydrous THF was added
under nitrogen dropwise over 2 h to a suspension of
6-amino-naphthalen-2-ol (3.02 g, 19.0 mmol), prepared in the
previous step, and triethylamine (2.20 mL, 15.8 mmol) in 300 mL of
anhydrous THF at ice bath temperature. After the addition the
reaction was stirred at ice bath temperature for 1 h. The ice bath
was removed and the stirring continued for 17 h (overnight). The
solid present was removed by filtration and the filtrate
concentrated to dryness under reduced pressure to give 6.70 g of a
brown foam. Purification of the foam on 600 g of silica (230-400
mesh) using 1% to 3% EtOAc in CH.sub.2Cl.sub.2 as the eluent gave
2-butyl-benzofuran-3-carboxylic acid
(6-hydroxy-naphthalen-2-yl)-amide (4.15 g, 73%) as a yellow solid,
mp 162-164.degree. C.
[0116] Elemental Analysis for C.sub.23H.sub.21NO.sub.3 Calc'd: C,
76.86; H, 5.89; N, 3.90 Found: C, 75.90; H, 5.84; N, 3.73
[0117] Step 6: 2-Butyl-benzofuran-3-carboxylic acid
(6-cyanomethoxy-naphthalen-2-yl)-amide. A mixture of
2-butyl-benzofuran-3-carboxylic acid
(6-hydroxy-naphthalen-2-yl)-amide (1.00 g, 2.79 mmol), prepared in
the previous step, bromoacetonitrile (583 .mu.L, 8.37 mmol) and
potassium carbonate (1.93 g, 13.97 mmol) in 25 mL of DMF was
stirred under nitrogen at room temperature for 23 h (overnight).
The reaction was partitioned between methylene chloride and water.
The organic layer was separated, washed four times with water, one
time with saturated NaCl, dried (MgSO.sub.4) and the solvent
removed under reduced pressure to give 1.27 g of a brown solid.
Purification of this solid on a 90 g KP-SIL 60 .DELTA. Biotage
column using methylene chloride as the eluent gave
2-butyl-benzofuran-3-carboxylic acid
(6-cyanomethoxy-naphthalen-2-yl)-amide (778 mg, 70%) as a light
yellow solid, mp 122-124.degree. C.
[0118] Elemental Analysis for C.sub.25H.sub.22N.sub.2O.sub.3
Calc'd: C, 75.36; H, 5.57; N, 7.03 Found: C, 75.23; H, 5.61; N,
6.95
[0119] Step 7: 2-Butyl-benzofuran-3-carboxylic acid
[6-(2H-tetrazol-5-ylmethoxy)-naphthalen-2-yl]-amide A mixture of
2-butyl-benzofuran-3-carboxylic acid
(6-cyanomethoxy-naphthalen-2-yl)-ami- de (301 mg, 0.756 mmol),
prepared in the previous step, sodium azide (147 mg, 2.25 mmol) and
ammonium chloride (121 mg, 2.27 mmol) in 15 mL of DMF was heated
under nitrogen at 100.degree. C. for 4 h. The reaction was diluted
with water, made basic by the addition of 1N NaOH and extracted
five times with ethyl acetate. The aqueous layer was then acidified
with 1 N HCl. The solid formed was collected by filtration, rinsed
with water and dried under reduced pressure to give the title
compound (116 mg, 34%) as an off-white solid, mp 194-198.degree.
C.
[0120] Elemental Analysis for C.sub.25H.sub.23N.sub.5O.sub.3+0.17
C.sub.3H.sub.7NO Calc'd: C, 67.50; H, 5.37; N, 15.95 Found: C,
66.57; H, 5.27; N, 15.88
EXAMPLE 4
{6-[(2-Butyl-benzofuran-3-carbonyl)-amino]-naphthalen-2-yloxy}-acetic
acid sodium salt
[0121] Step 1:
{6-[(2-Butyl-benzofuran-3-carbonyl)-amino]-naphthalen-2-ylo-
xy}-acetic acid methyl ester. A mixture of
2-butyl-benzofuran-3-carboxylic acid
(6-hydroxy-naphthalen-2-yl)amide (353 mg, 0.983 mmol), prepared in
step 5 of Example 3, methyl bromoacetate (93 .mu.L, 0.982 mmol) and
potassium carbonate (676 mg, 4.89 mmol) in 15 mL of DMF was stirred
under nitrogen at room temperature for 19 h (overnight). The
reaction was diluted with ethyl acetate, extracted five times with
water, dried (MgSO4) and the solvent removed under reduced pressure
to give 416 mg of a yellow solid. Purification of the solid on a 90
g KP-SIL 60 .DELTA. Biotage column using methylene chloride as the
eluent gave
{6-[(2-butyl-benzofuran-3-carbonyl)-amino]-naphthalen-2-yloxy}-acetic
acid methyl ester as a white solid, mp 131-133.degree. C.
[0122] Elemental Analysis for C.sub.26H.sub.25NO.sub.5 Calc'd: C,
72.37; H, 5.84; N, 3.25 Found: C, 72.32, H, 5.83; N, 3.21
[0123] Step 2:
{6-[(2-Butyl-benzofuran-3-carbonyl)-amino]-naphthalen-2-ylo-
xy}-acetic acid sodium salt. A mixture of
{6-[(2-butyl-benzofuran-3-carbon-
yl)-amino]-naphthalen-2-yloxy}-acetic acid methyl ester (103 mg,
0.239 mmol), prepared in the previous step, and 1 N NaOH (239
.mu.L, 0.239 mmol) in 10 mL of THF plus 5 mL of water was stirred
at room temperature for 21 h (overnight). The solvent was removed
under reduced pressure to give the title compound (95 mg, 87%) as a
yellow solid, MS m/z: 416 [M-H].sup.-.
[0124] Elemental Analysis for C.sub.25H.sub.22NO.sub.5Na+0.98
H.sub.2O Calc'd: C, 65.69; H, 5.28; N, 3.06 Found: C, 65.17; H,
5.30; N, 2.91
EXAMPLE 5
2-Butyl-benzofuran-3-carboxylic acid
[5-bromo-6-(2H-tetrazol-5-ylmethoxy)-- naphthalen-2-yl]-amide
[0125] Step 1: 2-Butyl-benzofuran-3-carboxylic acid
(5-bromo-6-hydroxy-naphthalen-2-yl)-amide. Bromine (287 .mu.L, 5.57
mmol) in 50 mL of glacial HOAc was added under nitrogen dropwise
over 3 h to a solution of 2-butyl-benzofuran-3-carboxylic acid
(6-hydroxy-naphthalen-2-- yl)-amide (2.00 g, 5.57 mmol), prepared
in step 5 of Example 3, in 100 mL of glacial HOAc at room
temperature. After the addition the reaction was stirred at room
temperature for 2 h. The solid formed was collected by filtration
and dried under reduced pressure to give 1.70 g of an off-white
solid. The solid was dissolved in 100 mL of 20%
MeOH--CH.sub.2Cl.sub.2 and chromatographed on 750 g of silica gel
(230-400 mesh) using methylene chloride as the eluent.
2-Butyl-benzofuran-3-carboxylic acid
(5-bromo-6-hydroxy-naphthalen-2-yl)-- amide 91.28 g, 52%) was
isolated as a light yellow solid, mp 195-197.degree. C.
[0126] Elemental Analysis for C.sub.23H.sub.20BrNO.sub.3 Calc'd: C,
63.03; H, 4.60; N, 3.20 Found: C, 62.66; H, 4.39; N, 3.10
[0127] Step 2: 2-Butyl-benzofuran-3-carboxylic acid
(5-bromo-6-cyanomethoxy-naphthalen-2-yl)-amide. A mixture of
2-butyl-benzofuran-3-carboxylic acid
(5-bromo-6-hydroxy-naphthalen-2-yl)-- amide (351 mg, 0.801 mmol),
prepared in the previous step, bromoacetonitrile (67 .mu.L, 0.962
mmol) and potassium carbonate (559 mg, 4.05 mmol) in 15 mL of DMF
was stirred under nitrogen at room temperature for 19 h
(overnight). The reaction was partitioned between ethyl acetate and
water. The organic layer was separated, washed five times with
water, dried (MgSO.sub.4) and the solvent removed under reduced
pressure to give 2-butyl-benzofuran-3-carboxylic acid
(5-bromo-6-cyanomethoxy-naphthalen-2- -yl)-amide (364 mg, 95%) as a
yellow solid, mp 155-159.degree. C.
[0128] Elemental Analysis for C.sub.25H.sub.21BrN.sub.2O.sub.3
Calc'd: C, 62.90; H, 4.43; N, 5.87 Found: C, 62.72; H, 4.40; N,
5.82
[0129] Step 3: 2-Butyl-benzofuran-3-carboxylic acid
[5-bromo-6-(2H-tetrazol-5-ylmethoxy)-naphthalen-2-yl]-amide. A
mixture of 2-butyl-benzofuran-3-carboxylic acid
(5-bromo-6-cyanomethoxy-naphthalen-2- -yl)-amide (266 mg, 0.557
mmol), prepared in the previous step, sodium azide (110 mg, 1.69
mmol) and ammonium chloride (90.2 mg, 1.69 mmol) in 15 ml of DMF
was stirred under nitrogen at 100.degree. C. for 5 h. The reaction
was diluted with water, made basic with 1 N NaOH and extracted five
times with ethyl acetate. The ethyl acetate extract was acidified
with 1 N HCl, filtered and the solvent concentrated under reduced
pressure and then diluted with water. The solid present was
collected by filtration, rinsed with water and dried under reduced
pressure to give the title compound (210 mg, 72%) as an off-white
solid, mp 242-245.degree. C.
[0130] Elemental Analysis for C.sub.25H.sub.22BrN.sub.5O.sub.3+0.27
H.sub.2O Calc'd: C, 57.17; H, 4.33; N, 13.33 Found: C, 56.58; H,
4.26; N, 12.69
EXAMPLE 6
{1-Bromo-6-[(2-butyl-benzofuran-3-carbonyl)-amino]-naphthalen-2-yloxy}-ace-
tic acid sodium salt
[0131] Step 1:
{1-Bromo-6-[(2-butyl-benzofuran-3-carbonyl)-amino]-naphthal-
en-2-yloxy}-acetic acid methyl ester. In the same manner as
described in step 5 of Example 1, and replacing
benzofuran-2-carboxylic acid
(6-hydroxy-naphthalen-2-ylmethyl)-amide with
2-butyl-benzofuran-3-carboxy- lic acid
(5-bromo-6-hydroxy-naphthalen-2-yl)-amide, prepared in step 1 of
Example 5, gave
{1-bromo-6-[(2-butyl-benzofuran-3-carbonyl)-amino]-naphth-
alen-2-yloxy}-acetic acid methyl ester (444 mg, 76%) was isolated
as a white solid, mp 179-181.degree. C.
[0132] Elemental Analysis for C.sub.26H.sub.24BrNO.sub.5 Calc'd: C,
61.19; H, 4.74; N, 2.74 Found: C, 60.81; H, 4.63; N, 2.79
[0133] Step 2:
{1-Bromo-6-[(2-butyl-benzofuran-3-carbonyl)-amino]-naphthal-
en-2-yloxy}-acetic acid sodium salt. In the same manner as
described in step 2 of Example 4 and replacing
{6-[(2-butyl-benzofuran-3-carbonyl)-ami-
no]-naphthalen-2-yloxy}-acetic acid methyl ester with
{1-bromo-6-[(2-butyl-benzofuran-3-carbonyl)-amino]-naphthalen-2-yloxy}-ac-
etic acid methyl ester, prepared in the previous step, gave the
title compound (289 mg, 94%) as a tan solid, mp 284-287.degree.
C.
[0134] Elemental Analysis for C.sub.25H.sub.21BrNO.sub.5Na+0.79
H.sub.2O Calc'd: C, 56.38; H, 4.27; N, 2.63 Found: C, 56.15; H,
4.16; N, 2.54
EXAMPLE 7
2-{1-Bromo-6-[(2-butyl-benzofuran-3-carbonyl)-amino]-naphthalen-2-yloxy}-3-
-phenyl-propionic acid
[0135] Step 1: 2-Hydroxy-3-phenyl-propionic acid methyl ester.
Hydrogen chloride was bubbled for 15 minutes into a solution of
2-hydroxy-3-phenyl-propionic acid (10.0 g, 60 mmol) in 100 mL of
methanol at room temperature. The vessel was sealed and then
stirred overnight at room temperature. The reaction was made basic
by the addition of 5% NaHCO.sub.3 and then concentrated under
reduced pressure to remove the methanol. The residue was diluted
with water and extracted with ethyl acetate. The organic layer was
extracted with saturated NaCl, dried (MgSO.sub.4) and the solvent
removed under reduced pressure to give 2-hydroxy-3-phenyl-propionic
acid methyl ester (9.7 g, 90%) as a yellow oil, MS m/z 180
[M].sup.+.
[0136] Elemental Analysis for C.sub.10H.sub.12O.sub.3 Calc'd: C,
66.65; H, 6.71; N, 0.00 Found: C, 66.52; H, 6.86; N, 0.29
[0137] Step 2: 3-Phenyl-2-trifluoromethanesulfonyloxy-propionic
acid methyl ester. Triethylamine (931 .mu.L, 6.68 mmol) was added
under nitrogen to a solution of 2-hydroxy-3-phenyl-propionic acid
methyl ester (1.00 g, 5.57 mmol), prepared in the previous step, in
20 mL of chloroform (99.9%; free of ethanol) at dry ice-acetone
temperature. Trifluoromethanesulfonic anhydride (1.03 mL, 6.13
mmol) was then added dropwise over 15 minutes. The cooling bath was
removed and the reaction was stirred overnight at room temperature.
The reaction was extracted with 1 N HCl, 5% NaHCO.sub.3, dried
(MgSO.sub.4) and the solvent removed under reduced pressure to give
1.53 g a brown oil. Purification of the oil on 100 g of silica gel
(230-400 mesh) using 3:1 methylene chloride-hexane as the eluent
gave 3-phenyl-2-trifluoromethanesulfonyloxy- -propionic acid methyl
ester (1.106 g, 64%) as clear oil.
[0138] Elemental Analysis for C,.sub.11H.sub.11F.sub.3O.sub.5S
Calc'd: C, 42.31; H, 3.55; N, 0.00 Found: C, 42.15; H, 3.35; N,
0.14
[0139] Step 3:
2-{1-Bromo-6-[(2-butyl-benzofuran-3-carbonyl)-amino]-naphth-
alen-2-yloxy}-3-phenyl-propionic acid methyl ester. A mixture of
2-butyl-benzofuran-3-carboxylic acid
(5-bromo-6-hydroxy-naphthalen-2-yl) amide (203 mg, 0.463 mmol),
prepared in step 1 of Example 5,
3-phenyl-2-trifluoromethanesulfonyloxypropionic acid methyl ester
(218 mg, 0.700 mmol), prepared in the previous step, and cesium
carbonate (303 mg, 0.929 mmol) in 25 mL of acetone was stirred
under nitrogen at room temperature for 21 h (overnight). The
acetone was removed under reduced pressure and the residue
partitioned between ethyl acetate and water. The organic layer was
separated and the aqueous layer extracted two times with ethyl
acetate. The combined extracts were dried (MgSO.sub.4) and the
solvent removed under reduced pressure to give 337 mg of a yellow
oil. Purification of the oil on 300 g of silica gel (230-400 mesh)
using methylene chloride as the eluent gave
2-{1-bromo-6-[(2-butyl-benzofuran-3-
-carbonyl)-amino]-naphthalen-2-yloxy}-3-phenyl-propionic acid
methyl ester (233 mg, 84%) [P6154-76-1] as an off-white solid, mp
136-139.degree. C.
[0140] Elemental Analysis for C.sub.33H.sub.30BrNO.sub.5 Calc'd: C,
66.00; H, 5.04; N, 2.33 Found: C, 66.02; H, 4.92; N, 2.27
[0141] Step 4:
2-{1-Bromo-6-[(2-butyl-benzofuran-3-carbonyl)-amino]-naphth-
alen-2-yloxy}-3-phenyl-propionic acid. A mixture of
2-{1-bromo-6-[(2-butyl-benzofuran-3-carbonyl)-amino]-naphthalen-2-yloxy}--
3-phenyl-propionic acid methyl ester (139 mg, 0.231 mmol), prepared
in the previous step, and 1 N NaOH (231 .mu.L, 0.231 mmol) in 75 mL
of methanol was refluxed for 4 h. By TLC starting material
remained. Water (10 mL) and 1 N NaOH (231 .mu.L, 0.231 mmol) were
added and the mixture refluxed for 18 h (overnight). The reaction
was filtered and 2 mL of 1 N HCL was added to the filtrate. The
filtrate was concentrated under reduced pressure to remove the
methanol. The solid formed was collected by filtration, rinsed with
water and dried under reduced pressure to give the title compound
(111 mg, 81%) as a white solid, mp 191-195.degree. C.
[0142] Elemental Analysis for C.sub.32H.sub.28BrNO.sub.5+0.19
H.sub.2O Calc'd: C, 65.16; H, 4.85; N, 2.37 Found: C, 65.36; H,
4.59; N, 2.36
EXAMPLE 8
2-Butyl-benzofuran-3-carboxylic acid
[6-(1H-tetrazol-5-ylmethoxy)-naphthal- en-2-ylmethyl]-amide sodium
salt
[0143] Step 1: 6-Aminomethyl-naphthalen-2-ol. A mixture of
C-(6-methoxy-naphthalen-2-yl)-methylamine (10.78 g, 57.6 mmol),
prepared in step 1 of Example 1, and 350 mL of 48% HBr was refluxed
for 3 h. The solvent was removed under reduced pressure give 13.48
g of a dark brown solid. The solid was dissolved in approximately
500 mL of water, made basic by the addition of 5% NaHCO.sub.3 and
filtered. The filtrate was extracted multiple times with ethyl
acetate. The combined organic extracts were dried (MgSO.sub.4) and
the solvent removed under reduced pressure to give
6-aminomethyl-naphthalen-2-ol (3.4 g, 30%) as an off-white solid,
mp 188-192.degree. C.
[0144] Elemental Analysis for C.sub.11H.sub.11NO0.1 H2O+0.05 EtOAc
Calc'd: C, 74.98; H, 6.52; N, 7.81 Found: C, 73.74; H, 6.44; N,
7.50
[0145] Step 2: 2-Butyl-benzofuran-3-carboxylic acid
(6-hydroxy-naphthalen-2-ylmethyl)-amide.
2-Butyl-benzofuran-3-carbonyl chloride (1.54 g, 6.5 mmol), prepared
in step 2 of Example 3, in 45 mL of anhydrous THF was added under
nitrogen dropwise over 2 h to a solution of
6-aminomethyl-naphthalen-2-ol (1.13 g, 6.5 mmol), prepared in the
previous step, and triethylamine (906 .mu.L, 6.5 mmol) in 150 mL of
anhydrous THF at room temperature. After the addition the reaction
was stirred at room temperature for 20 h (overnight). The solid was
removed by filtration and the filtrate concentrated under reduced
pressure to give 2.50 g of a brown oil. Purification of the oil on
a 90 g KP-SIL 60 .DELTA. Biotage column using 3:1 hexane:ethyl
acetate as the eluent gave 2-butyl-benzofuran-3-carboxylic acid
(6-hydroxy-naphthalen-2-ylmethyl)-am- ide (1.88 g, 78%) as a white
solid, mp 155-156.degree. C.
[0146] Elemental Analysis for C.sub.24H.sub.23NO.sub.3 Calc'd: C,
77.19; H, 6.21; N, 3.75 Found: C, 76.99; H, 6.07; N, 3.76
[0147] Step 3: 2-Butyl-benzofuran-3-carboxylic acid
(6-cyanomethoxy-naphthalen-2-ylmethyl)-amide. A mixture of
2-butyl-benzofuran-3-carboxylic acid
(6-hydroxy-naphthalen-2-ylmethyl)-am- ide (402 mg, 0.974 mmol),
prepared in the previous step, bromoacetonitrile (204 .mu.L, 2.9
mmol) and potassium carbonate (673 mg, 4.87 mmol) in 10 mL of DMF
was stirred under nitrogen at room temperature for 20 h
(overnight). The reaction was diluted with methylene chloride,
extracted multiple times with water, dried (MgSO.sub.4) and the
solvent removed under reduced pressure to give 413 mg of an
off-white solid. Recrystallization of the solid from isopropyl
alcohol gave 2-butyl-benzofuran-3-carboxylic acid
(6-cyanomethoxy-naphthalen-2-ylmethy- l)-amide (349 mg, 87%) as a
white solid, mp 142-143.degree. C.
[0148] Elemental Analysis for C.sub.26H.sub.24N.sub.2O.sub.3
Calc'd: C, 75.71; H, 5.86; N, 6.79 Found: C, 75.66; H, 5.87; N,
6.84
[0149] Step 4: 2-Butyl-benzofuran-3-carboxylic acid [6-(1
tetrazol-5-ylmethoxy)-naphthalen-2-ylmethyl]-amide sodium salt. A
mixture of 2-butyl-benzofuran-3-carboxylic acid
(6-cyanomethoxy-naphthalen-2-ylme- thyl)-amide (200 mg, 0.485
mmol), prepared in the previous step, sodium azide (94 mg, 1.45
mmol) and ammonium chloride (77 mg, 1.45 mmol) in 10 mL of DMF was
stirred under nitrogen at 100.degree. C. for 5 h. The reaction was
diluted with water, made basic by the addition of 1 N NaOH and
extracted two times with ethyl acetate. At this point a solid was
present in the aqueous layer. The solid was collected by filtration
and dried under reduced pressure to give the title compound (134
mg, 54%) as a white solid, mp 207-210.degree. C.
[0150] Elemental Analysis for C.sub.26H.sub.24N.sub.5O.sub.3Na+1.87
H2O Calc'd: C, 61.09; H, 5.47; N, 13.70 Found: C, 59.38; H, 5.28;
N, 13.38
EXAMPLE 9
Sodium;
(6-{1[(2-butyl-benzofuran-3-carbonyl)-amino]-methyl}-naphthalen-2--
yloxy)-acetate
[0151] Step 1:
(6-{[(2-Butyl-benzofuran-3-carbonyl)-amino]-methyl}-naphtha-
len-2-yloxy)-acetic acid methyl ester. A mixture of
2-butyl-benzofuran-3-carboxylic acid
(6-hydroxy-naphthalen-2-ylmethyl)-am- ide (500 mg, 1.34 mmol),
prepared in step 2 of Example 8, methyl bromoacetate (127 .mu.L,
1.34 mmol) and potassium carbonate (926 mg, 6.7 mmol) in 25 mL of
DMF was stirred under nitrogen at room temperature overnight. The
reaction was diluted with ethyl acetate, extracted multiple times
with water, dried (MgSO.sub.4) and the solvent removed under
reduced pressure to give 573 mg of a tan solid. Recrystallization
of the solid from isopropyl alcohol gave
(6-{[(2-butyl-benzofuran-3-carbo-
nyl)-amino]-methyl}-naphthalen-2-yloxy)-acetic acid methyl ester
(411 mg, 69%) as a white solid, mp 142-143.degree. C.
[0152] Elemental Analysis for C.sub.27H.sub.27NO.sub.5 Calc'd: C,
72.79; H, 6.11; N, 3.14 Found: C, 72.61; H, 6.13; N, 3.13
[0153] Step 2: Sodium;
(6-{[(2-butyl-benzofuran-3-carbonyl)-amino]-methyl}-
-naphthalen-2-yloxy)-acetate. 1 N NaOH (449 .mu.L, 0.449 mmol) was
added to a solution of
(6-{[(2-butyl-benzofuran-3-carbonyl)-amino]-methyl}-naph-
thalen-2-yloxy)-acetic acid methyl ester (200 mg, 0.449 mmol),
prepared in the previous step, in 30 mL of THF plus 15 mL of water
at room temperature. After the addition the reaction was stirred at
room temperature overnight. The solvent was removed under reduced
pressure to give the title compound (209 mg, 99%) as a white solid,
mp >275.degree. C., MS m/z 430 [M-H].sup.-.
[0154] Elemental Analysis for C.sub.26H.sub.25NO.sub.5Na+1.2
H.sub.2O Calc'd: C, 65.59; H, 5.80; N, 2.94 Found: C, 65.24; H,
5.58; N, 2.91
EXAMPLE 10
[6-({[5-(4-Chloro-phenyl)-2-methyl-furan-3-carbonyl]-amino}-methyl)-naphth-
alen-2-yloxy]-acetic acid
[0155] Step 1: 5-(4-Chloro-phenyl)-2-methyl-furan-3-carboxylic acid
(6-hydroxy-naphthalen-2-ylmethyl)-amide.
5-(4-Chloro-phenyl)-2-methyl-fur- an-3-carbonyl chloride (737 mg,
2.89 mmol) in 25 mL of methylene chloride was added under nitrogen
dropwise over 30 minutes to a suspension of
6-aminomethyl-naphthalen-2-ol (500 mg, 2.89 mmol), prepared in step
1 of Example 8, in 25 mL of anhydrous pyridine at ice bath
temperature. After the addition the ice bath was removed and the
reaction stirred at room temperature overnight. The reaction was
partitioned between methylene chloride and 1 N HCl. The organic
layer was separated and the aqueous layer was extracted with
methylene chloride. The combined extracts were dried (MgSO.sub.4)
and the solvent removed under reduced pressure to give 1.04 g of a
brown solid. Purification of the solid on 500 g of silica gel
(230-400 mesh) using 10% ethyl acetate-methylene chloride as the
eluent gave 5-(4-chloro-phenyl)-2-methyl-furan-3-carboxylic acid
(6-hydroxy-naphthalen-2-ylmethyl)-amide (507 mg, 45%) as a tan
solid, mp 202-204.degree. C.
[0156] Elemental Analysis for C.sub.23H.sub.18ClNO.sub.3 Calc'd: C,
70.50; H, 4.63; N, 3.57 Found: C, 69.25; H, 4.67; N, 3.49
[0157] Step 2:
[6-({[5-(4-Chloro-phenyl)-2-methyl-furan-3-carbonyl]-amino}-
-methyl)-naphthalen-2-yloxy]-acetic acid methyl ester. A mixture of
5-(4-chloro-phenyl)-2-methyl-furan-3-carboxylic acid
(6-hydroxy-naphthalen-2-ylmethyl)-amide (405 mg, 1.03 mmol),
prepared in the previous step, methyl bromoacetate (98 .mu.L, 1.03
mmol) and potassium carbonate (710 mg, 5.15 mmol) in 10 mL of DMF
was stirred under nitrogen at room temperature overnight. The
reaction was diluted with ethyl acetate, extracted multiple times
with water, one time with saturated NaCl, dried (MgSO.sub.4) and
the solvent removed under reduced pressure to give 450 mg of a
yellow solid. Recrystallization of the solid from isopropyl alcohol
gave [6-({[5-(4-chloro-phenyl)-2-methyl-furan-3-ca-
rbonyl]-amino}-methyl)-naphthalen-2-yloxy]-acetic acid methyl ester
(280 mg, 58%) as an off-white solid, mp 168-169.degree. C.
[0158] Elemental Analysis for C.sub.26H.sub.22ClNO.sub.5 Calc'd: C,
67.32; H, 4.78; N, 3.02 Found: C, 66.86; H, 4.69; N, 2.98
[0159] Step 3:
[6-({[5-(4-Chloro-phenyl)-2-methyl-furan-3-carbonyl]-amino}-
-methyl)-naphthalen-2-yloxy]-acetic acid. 1 N NaOH (514 .mu.L,
0.514 mmol) was added under nitrogen to a solution of
[6-({[5-(4-chloro-phenyl)-2-met-
hyl-furan-3-carbonyl]-amino}-methyl)-naphthalen-2-yloxy]-acetic
acid methyl ester (239 mg, 0.514 mmol), prepared in the previous
step, in 30 mL of THF plus 15 mL of water. After the addition the
reaction was stirred at room temperature for 20 h (overnight). 1 N
HCl (1 mL) was added and the reaction then concentrated under
reduced pressure to remove the THF. The solid present was removed
by filtration and dried under reduced pressure to give the title
compound (190 mg, 83%) as a tan solid, mp 177-181.degree. C.
[0160] Elemental Analysis for C.sub.25H.sub.20ClNO.sub.5+0.34
H.sub.2O Calc'd: C, 65.85; H, 4.57; N, 3.07 Found: C, 65.74; H,
4.82; N, 2.84
EXAMPLE 11
[6-({[5-(4-Chloro-phenyl)-2-trifluoromethyl-furan-3-carbonyl]-amino}-methy-
l)-naphthalen-2-yloxy]-acetic acid
[0161] Step 1:
5-(4-Chloro-phenyl)-2-trifluoromethyl-furan-3-carboxylic acid
(6-hydroxy-naphthalen-2-ylmethyl)-amide. In the same manner as
described in step 1 of Example 10, and replacing
5-(4-chloro-phenyl)-2-me- thyl-furan-3-carbonyl chloride with
5-(4-chloro-phenyl)-2-trifluoromethyl-- furan-3-carbonyl chloride,
gave 5-(4-chloro-phenyl)-2-trifluoromethyl-fura- n-3-carboxylic
acid (6-hydroxy-naphthalen-2-ylmethyl)-amide (691 mg, 32%) as a tan
powder, mp 189-191.degree. C.
[0162] Elemental Analysis for
C.sub.23H.sub.15ClF.sub.3NO.sub.3+0.39 CH.sub.2Cl.sub.2 Calc'd: C,
58.66; H, 3.32; N, 2.92 Found: C, 57,76; H, 3.09; N. 2.79
[0163] Step 2:
[6-({[5-(4-Chloro-phenyl)-2-trifluoromethyl-furan-3-carbony-
l]-amino}-methyl)-naphthalen-2-yloxy]-acetic acid methyl ester. A
mixture of 5-(4-chloro-phenyl)-2-trifluoromethyl-furan-3-carboxylic
acid (6-hydroxy-naphthalen-2-ylmethyl)-amide (300 mg, 0.67 mmol),
prepared in the previous step, methyl bromoacetate (64 .mu.L, 0.67
mmol) and potassium carbonate (465 mg, 3.37 mmol) in 10 mL of DMF
was stirred under nitrogen at room temperature overnight. The
reaction was diluted with ethyl acetate, extracted multiple times
with water, dried (MgSO.sub.4) and the solvent removed under
reduced pressure to give 284 mg of a yellow solid.
Recrystallization of this solid from isopropyl alcohol gave
[6-({[5-(4-chloro-phenyl)-2-trifluoromethyl-furan-3-carbonyl]-amino}-meth-
yl)-naphthalen-2-yloxy]-acetic acid methyl ester (204 mg, 59%) as a
white solid, mp 182-183.degree. C.
[0164] Elemental Analysis for C.sub.26H.sub.19CIF.sub.3NO.sub.5
Calc'd: C, 60.30; H, 3.70; N, 2.70 Found: C, 60.09; H, 3.52; N,
2.69
[0165] Step 3:
[6-({[5-(4-Chloro-phenyl)-2-trifluoromethyl-furan-3-carbony-
l]-amino}-methyl)-naphthalen-2-yloxy]-acetic acid. 1 N NaOH (324
.mu.L, 0.32 mmol) was added under nitrogen to a solution at room
temperature of
[6-({[5-(4-chloro-phenyl)-2-trifluoromethyl-furan-3-carbonyl]-amino}-meth-
yl)-naphthalen-2-yloxy]-acetic acid methyl ester (140 mg, 0.27
mmol), prepared in the previous step, in 15 mL of THF plus 8 mL of
water. After the addition the reaction was stirred at room
temperature for 7 h. The reaction was acidified with 1 N HCl and
then concentrated under reduced pressure to remove the THF. The
solid present was collected by filtration and dried under reduced
pressure to give the title compound (125 mg, 91%) as an off-white
solid, mp 194-196.degree. C.
[0166] Elemental Analysis for C.sub.25H.sub.17ClF.sub.3NO.sub.5+0.4
H.sub.2O Calc'd: C, 58.75; H, 3.51; N, 2.74 Found: C, 58.83; H,
3.59; N, 2.56
EXAMPLE 12
(6-{[(1-phenyl-5-propyl-1H-pyrazole-4-carbonyl)-amino]-methyl}-naphthalen--
2-yloxy)-acetic acid
[0167] Step 1: 1-Phenyl-5-propyl-1H-pyrazole-4-carboxylic acid
(6-hydroxy-naphthalen-2-ylmethyl)-amide.
1-Phenyl-5-propyl-1H-pyrazole-4-- carbonyl chloride (2.0 g, 8.0
mmol) in 20 mL of methylene chloride was added under nitrogen at
room temperature to a suspension of 6-aminomethyl-naphthalen-2-ol
(1.63 g, 9.42 mmol), prepared in step 1 of Example 8, in 75 mL of
anhydrous pyridine. After the addition the reaction was stirred at
room temperature for 17 h (overnight). The reaction was partitioned
between methylene chloride and 1 N HCl. The organic layer was
separated and the aqueous layer extracted multiple times with
methylene chloride. The combined extracts were dried (MgSO.sub.4)
and the solvent removed under reduced pressure to give 1.9 g of a
brown solid. Recrystallization of the solid one time from ethyl
acetate and one time from isopropyl alcohol gave
1-phenyl-5-propyl-1H-pyr- azole-4-carboxylic acid
(6-hydroxy-naphthalen-2-ylmethyl)-amide (767 mg, 25%) as a tan
solid, mp 189-190.degree. C.
[0168] Elemental Analysis for C.sub.24H.sub.23N.sub.3O.sub.2
Calc'd: C, 74.78; H, 6.01; N, 10.90 Found: C, 73.64; H, 5.78; N,
10.77
[0169] Step 2:
(6-{[(1-Phenyl-5-propyl-1H-pyrazole-4-carbonyl)-amino]-meth-
yl}-naphthalen-2-yloxy)-acetic acid methyl ester. A mixture of
1-phenyl-5-propyl-1H-pyrazole-4-carboxylic acid
(6-hydroxy-naphthalen-2-y- lmethyl)-amide (300 mg, 0.778 mmol),
prepared in the previous step, methyl bromoacetate (74 .mu.L, 0.778
mmol) and potassium carbonate (540 mg, 3.89 mmol) in 10 mL of DMF
was stirred under nitrogen at room temperature for 18 h
(overnight). The reaction was diluted with ethyl acetate, extracted
multiple times with water, one time with saturated NaCl, dried
(MgSO.sub.4) and the solvent removed under reduced pressure to give
299 mg of an off-white solid. Recrystallization of the solid from
isopropyl alcohol gave
(6-{[(1-phenyl-5-propyl-1H-pyrazole-4-carbony)-amino]-methyl-
}-naphthalen-2-yloxy)-acetic acid methyl ester (208 mg, 57%) as a
white solid, mp 145-146.degree. C.
[0170] Elemental Analysis for C.sub.27H.sub.27N.sub.3O.sub.4
Calc'd: C, 70.88; H, 5.95; N, 9.18 Found: C, 70.73; H, 5.76; N,
9.15
[0171] Step 3:
(6-{[(1-phenyl-5-propyl-1H-pyrazole-4-carbonyl)-amino]-meth-
yl}-naphthalen-2-yloxy)-acetic acid. 1 N NaOH (431 .mu.L, 0.431
mmol) was added under nitrogen to a solution at room temperature of
(6-{[(1-phenyl-5-propyl-1H-pyrazole-4-carbonyl)-amino]-methyl}-naphthalen-
-2-yloxy)-acetic acid methyl ester (170 mg, 0.359 mmol), prepared
in the previous step, in 25 mL of MeOH plus 10 mL of water. After
the addition the reaction was stirred at room temperature for 18 h
(overnight). The reaction was acidified with 1 N HCl and then
concentrated under reduced pressure to remove the MeOH. The solid
present was collected by filtration and dried under reduced
pressure to give the title compound (146 mg, 92%) as an off-white
solid, mp 175-177.degree. C.
[0172] Elemental Analysis for C.sub.26H.sub.25N.sub.3O.sub.4+0.25
H.sub.2O Calc'd: C, 69.71; H, 5.74; N, 9.38 Found: C, 68.99; H,
5.73; N, 9.20
EXAMPLE 13
[6-({[1-(4-Chloro-phenyl)-5-propyl-1H-pyrazole-4-carbonyl]-amino}-methyl)--
naphthalen-2-yloxy]-acetic acid
[0173] Step 1: (6-Hydroxy-naphthalen-2-ylmethyl)-carbamic acid
tert-butyl ester. A solution of di-tert-butyl dicarbonate (3.13 g,
14.36 mmol) in 25 mL of anhydrous DMF was added dropwise under
nitrogen over 30 minutes to a mixture of
6-hydroxy-naphthalen-2-ylmethyl-ammonium; bromide (3.65 g, 14.36
mmol), prepared in step 2 of Example 1, and triethylamine (2.0 mL,
14.36 mmol) in 75 mL of anhydrous DMF. The reaction was stirred at
room temperature for 18 h (overnight). The reaction was diluted
with ethyl acetate and extracted two times with 1N HCl and four
times with water. The organic layer was dried (MgSO.sub.4) and the
solvent removed under reduced pressure to give an oily brown solid.
Purification of the material on a 90 g KP-SIL 60.DELTA. Biotage
column using 3% ethyl acetate in methylene chloride as the eluent
gave (6-hydroxy-naphthalen-2-ylmethyl- )-carbamic acid tert-butyl
ester (917 mg, 23%) as a yellow solid, mp 173-174.degree. C.
[0174] Elemental Analysis for C.sub.16H.sub.19NO.sub.3 Calc'd: C,
70.31; H, 7.01; N, 5.12 Found: C, 69.36; H, 7.08; N, 5.08
[0175] Step 2:
[6-tert-Butoxycarbonylamino-methyl)-naphthalen-2-yloxy]-ace- tic
acid methyl ester. A mixture of
(6-hydroxy-naphthalen-2-ylmethyl)-carb- amic acid tert-butyl ester
(5.127 g, 18.77 mmol), prepared in the previous step, methyl
bromoacetate (1.78 mL, 18.77 mmol) and potassium carbonate (13.0 g,
93.85 mmol) in 100 mL of DMF was stirred under nitrogen at room
temperature for 17 h (overnight). The reaction was diluted with
ethyl acetate, extracted four times with water, dried (MgSO.sub.4)
and the solvent removed under reduced pressure to give a yellow
solid. Recrystallization of the solid from isopropyl alcohol gave
[6-tert-butoxycarbonylamino-methyl)-naphthalen-2-yloxy]-acetic acid
methyl ester (1.8 g, 28%) as a white solid, mp 182-183.degree.
C.
[0176] Elemental Analysis for C.sub.26H.sub.19ClF.sub.3NO.sub.5
Calc'd: C, 60.30; H, 3.70; N, 2.70 Found: C, 60.09; H, 3.52; N,
2.69
[0177] Step 3:
6-Methoxycarbonyl-methoxy-naphthalen-2-ylmethyl-ammonium; chloride.
A solution of 75 mL of ethyl acetate saturated with hydrogen
chloride gas was added under nitrogen to
[6-tert-butoxycarbonylamino-meth- yl)-naphthalen-2-yloxy]-acetic
acid methyl ester (1.01 g, 2.924 mmol), prepared in the previous
step. Within one minute a solid precipitated from solution. The
reaction stirred for 18 h (overnight). The solid was collected by
filtration, rinsed with ethyl acetate and dried under reduced
pressure to give 6-methoxycarbonyl-methoxy-naphthalen-2-ylmethyl--
ammonium; chloride (0.79 g, 95.8%) as an off white solid, mp
240-241.degree. C.
[0178] Elemental Analysis for C.sub.14H.sub.16ClNO.sub.3+0.02 mol
H.sub.2O Calc'd: C, 59.61; H, 5.73; N, 4.79 Found: C, 59.04; H,
5.72; N, 4.82
[0179] Step 4:
[6-({[1-(4-Chloro-phenyl)-5-propyl-1H-pyrazole-4-carbonyl]--
amino}-methyl)-naphthalen-2-yloxy]-acetic acid methyl ester.
Triethylamine (300 .mu.L, 2.13 mmol) was added under nitrogen to a
suspension of
6-methoxycarbonylmethoxy-naphthalen-2-ylmethyl-ammonium; chloride
(300 mg, 1.06 mmol), prepared in the prervious step, and
1-(4-chloro-phenyl)-5-propyl-1H-pyrazole-4-carbonyl chloride (301
mg, 1.06 mmol) in 20 mL of methylene chloride at room temperature.
After the addition the reaction was stirred at room temperature
overnight. The reaction was diluted with methylene chloride and
then extracted with water, 5% NaHCO.sub.3, dried (MgSO.sub.4) and
the solvent removed under reduced pressure to give 480 mg of an
off-white solid. Recrystallization of the solid from ethyl acetate
gave [6-({[1-(4-chloro-phenyl)-5-propyl-1-
H-pyrazole-4-carbonyl]-amino}-methyl)-naphthalen-2-yloxy]-acetic
acid methyl ester (397 mg, 76%) as a white solid, mp
139-140.degree. C.
[0180] Elemental Analysis for C.sub.27H.sub.26ClN.sub.3O.sub.4
Calc'd: C, 65.92; H, 5.33; N, 8.54 Found: C, 65.74; H, 5.14; N,
8.51
[0181] Step 5:
[6-({[1-(4-Chloro-phenyl)-5-propyl-1H-pyrazole-4-carbonyl]--
amino}-methyl)-naphthalen-2-yloxy]-acetic acid. 1 N NaOH (335
.mu.L, 0.335 mmol) was added under nitrogen to a solution of
[6-({[1-(4-chloro-phenyl)-
-5-propyl-1H-pyrazole-4-carbonyl]-amino}-methyl)-naphthalen-2-yloxy]-aceti-
c acid methyl ester (150 mg, 0.305 mmol), prepared in the previous
step, in 25 mL of MeOH plus 10 mL of water at room temperature.
After the addition the reaction was stirred at room temperature for
20 h (overnight). The reaction was acidified by the addition of 1 N
HCl and then concentrated under reduced pressure to remove the
MeOH. The solid present was collected by filtration and dried under
reduced pressure to give the title compound (138 mg, 94%) as a pink
solid, mp 203-204.degree. C.
[0182] Elemental Analysis for C.sub.26H.sub.24N.sub.3O.sub.4Cl+0.22
H.sub.2O+0.26 CH.sub.3OH Calc'd: C, 64.34; H, 5.24; N, 8.57 Found:
C, 64.03; H, 4.94; N, 8.51
EXAMPLE 14
[6-({[1-(4-Chloro-phenyl)-5-trifluoromethyl-1H-pyrazole-4-carbonyl]-amino}-
-methyl)-naphthalen-2-yloxy]-acetic acid
[0183] Step 1:
[6-({[1-(4-Chloro-phenyl)-5-trifluoromethyl-1H-pyrazole-4-c-
arbonyl]-amino}-methyl)-naphthalen-2-yloxy]-acetic acid methyl
ester. Triethylamine (300 .mu.L, 2.13 mmol) was added under
nitrogen to a suspension of
6-methoxycarbonylmethoxy-naphthalen-2-ylmethyl-ammonium; chloride
(300 mg, 1.06 mmol), prepared in step 3 of Example 13, and
1-(4-chloro-phenyl)-5-trifluoromethyl-1H-pyrazole-4-carbonyl
chloride (330 mg, 1.06 mmol) in 20 mL of methylene chloride at room
temperature. After the addition the reaction was stirred at room
temperature overnight. The reaction was diluted with methylene
chloride and then extracted with water, 5% NaHCO.sub.3, dried
(MgSO.sub.4) and the solvent removed under reduced pressure to give
518 mg of a brown solid. Recrystallization of the solid from
isopropyl alcohol gave
[6-({[1-(4-chloro-phenyl)-5-trifluoromethyl-1H-pyrazole-4-carbonyl]-amino-
}-methyl)-naphthalen-2-yloxy]-acetic acid methyl ester (479 mg,
87%) as a tan solid, mp 174-176.degree. C.
[0184] Elemental Analysis for
C.sub.25H.sub.19ClF.sub.3N.sub.3O.sub.4 Calc'd: C, 57.98; H, 3.70;
N, 8.11 Found: C, 57.95; H, 3.66; N, 8.15
[0185] Step 2:
[6-({[1-(4-Chloro-phenyl)-5-trifluoromethyl-1H-pyrazole-4-c-
arbonyl]-amino}-methyl)-naphthalen-2-yloxy]-acetic acid. 1 N NaOH
(563 .mu.L, 0.563 mmol) was added under nitrogen to
[6-({[1-(4-chloro-phenyl)--
5-trifluoromethyl-1H-pyrazole-4-carbonyl]-amino}-methyl)-naphthalen-2-ylox-
y]-acetic acid methyl ester (243 mg, 0.469 mmol), prepared in the
previous step, in 100 mL of MeOH plus 25 mL of water at room
temperature. After the addition the reaction was stirred at room
temperature overnight. The reaction was acidified by the addition
of 1 N HCl and then concentrated under reduced pressure to remove
the MeOH. The solid present was collected by filtration and dried
under reduced pressure to give the title compound (210 mg, 89%) as
a pink solid, mp 189-191.degree. C.
[0186] Elemental Analysis for
C.sub.24H.sub.17ClF.sub.3N.sub.3O.sub.4+0.68 H.sub.2O Calc'd: C,
55.85; H, 3.59; N, 8.14 Found: C, 55.52; H, 3.23; N, 8.05
EXAMPLE 15
(1-Bromo-6-{[(1-phenyl-5-propyl-1H-pyrazole-4-carbonyl)-amino]-methyl}-nap-
hthalen-2-yloxy)-acetic acid
[0187] Step 1: (5-Bromo-6-hydroxy-naphthalen-2-ylmethyl)-carbamic
acid tert-butyl ester. A solution of benzyltrimethylammoniumbromide
(1.755 g, 4.5 mmol) in 50 mL of methylene chloride was added
dropwise under nitrogen over 2 h to a mixture of
(6-hydroxy-naphthalen-2-ylmethyl)-carba- mic acid tert-butyl ester
(1.24 g, 4.5 mmol), prepared in step 1 of Example 13, and calcium
carbonate (1.35 g, 13.5 mmol) in 150 mL of methylene chloride plus
60 mL of methanol at room temperature. The reaction was stirred for
20 h (overnight). The reaction was diluted with water and extracted
three times with methylene chloride. The organic extracts were
combined, dried (MgSO.sub.4) and the solvent removed under reduced
pressure to give 1.4 g of a yellow solid. The solid was
recrystallized from 15 mL of isopropyl alcohol. The crystals were
collected by filtration and dried under reduced pressure to give
(5-bromo-6-hydroxy-naphthalen-2-ylmethyl)-carbamic acid tert-butyl
ester (0.95 g, 60%) as an off white solid, mp 150-152.degree.
C.
[0188] Elemental Analysis for C.sub.16H.sub.18BrNO.sub.3 Calc'd: C,
54,56; H, 5.15; N, 3.98 Found: C, 54.22; H, 4.84; N, 3.82
[0189] Step 2:
[1-Bromo-6-(tert-butoxycarbonylamino-methyl)-naphthalen-2-y-
loxy]-acetic acid methyl ester. A mixture of
(5-bromo-6-hydroxy-naphthalen- -2-ylmethyl)-carbamic acid
tert-butyl ester (0.89 g, 2.5 mmol), prepared in the previous step,
potassium carbonate (1.7 g, 12.5 mmol), and methyl bromoacetate
(1.26 mL, 2.75 mmol) in 10 mL of DMF was stirred under nitrogen for
18 h (overnight). The reaction was diluted with ethyl acetate and
extracted three times with water. The organic layer was dried
(MgSO.sub.4) and the solvent removed under reduced pressure to give
[1-bromo-6-(tert-butoxycarbonylamino-methyl)-naphthalen-2-yloxy]-acetic
acid methyl ester (1.016 g, 96%) as an off white solid, mp
96-100.degree. C.
[0190] Elemental Analysis for C.sub.19H.sub.22BrNO.sub.5 Calc'd: C,
53.79; H, 5.23; N, 3.30 Found: C, 53.86; H, 5.24; N, 3.27
[0191] Step 3:
5-Bromo-6-methoxycarbonylmethoxy-naphthalen-2-ylmethyl-ammo- nium;
chloride. A solution of 75 mL of ethyl acetate saturated with
hydrogen chloride gas was added under nitrogen at room temperature
to
[1-bromo-6-(tert-butoxycarbonylamino-methyl)-naphthalen-2-yloxy]-acetic
acid methyl ester (0.934 g, 2.2 mmol), prepared in the previous
step. A precipitate formed within one minute. The reaction stirred
for 17 h (overnight). The solid was collected by filtration, rinsed
with ethyl acetate, and dried under reduced pressure to give
5-bromo-6-methoxycarbon- ylmethoxy-naphthalen-2-ylmethyl-ammonium;
chloride (0.696 g, 88%) as an off white solid, mp 261-263.degree.
C.
[0192] Elemental Analysis for C.sub.14H.sub.14BrNO.sub.3+HCl
Calc'd: C, 46.63; H, 4.19; N, 3.88 Found: C, 46.41; H, 4.01; N,
3.82
[0193] Step 4:
(1-Bromo-6-{[(1-phenyl-5-propyl-1H-pyrazole-4-carbonyl)-ami-
no]-methyl}-naphthalen-2-yloxy)-acetic acid methyl ester.
Triethylamine (0.192 mL, 1.38 mmol) was added under nitrogen to a
mixture of
5-bromo-6-methoxycarbonylmethoxy-naphthalen-2-ylmethyl-ammonium;
chloride (0.25 g, 0.69 mmol), prepared in the previous step, and
1-phenyl-5-propyl-1H-pyrazole-4-carbonyl chloride (0.17 g, 0.69
mmol) in 20 mL of methylene chloride at room temperature. The
reaction stirred under nitrogen for 17 h. The reaction was diluted
with methylene chloride, extracted two times with water, two times
with 5% sodium bicarbonate, dried (MgSO.sub.4) and the solvent
removed under reduced pressure to give
(1-Bromo-6-{[(1-phenyl-5-propyl-1H-pyrazole-4-carbonyl)--
amino]-methyl}-naphthalen-2-yloxy)-acetic acid methyl ester (0.347
g, 95%) as a white solid, mp 144-146.degree. C.
[0194] Elemental Analysis for C.sub.27H.sub.26BrN.sub.3O.sub.4
Calc'd: C, 60.46; H, 4.89; N, 7.83 Found: C, 60.74; H, 4.60; N,
7.80
[0195] Step 5:
(1-Bromo-6-{[(1-phenyl-5-propyl-1H-pyrazole-4-carbonyl)-ami-
no]-methyl}-naphthalen-2-yloxy)-acetic acid. A mixture of
(1-bromo-6-{[(1-phenyl-5-propyl-1H-pyrazole-4-carbonyl)-amino]-methyl}-na-
phthalen-2-yloxy)-acetic acid methyl ester (0.20 g, 0.373 mmol),
prepared in the previous step, 1N NaOH (373 .mu.L, 0.373 mmol), 5
mL of water and 60 mL of methanol was stirred at room temperature
for 20 h. Starting material was present by TLC. An additional 186
.mu.L (0.186 mmol) of 1N NaOH was added and the reaction stirred at
room temperature for 18 h. The reaction was filtered to remove
trace solids and acidified with 1N HCl until pH 1 by litmus paper.
The methanol was removed under reduced pressure. The solid formed
was collected by filtration and dried under reduced pressure to
give the title compound (0.13 g, 67%) as an off-white solid, mp
140-145.degree. C.
[0196] Elemental Analysis for C.sub.26H.sub.24BrN.sub.3O.sub.4+0.71
H.sub.2O Calc'd: C, 58.35; H, 4.79; N, 7.85 Found: C, 58.05; H,
4.58; N, 7.63
EXAMPLE 16
[1-Bromo-6-({[1-(4-chloro-phenyl)-5-trifluoromethyl-1H-pyrazole-4-carbonyl-
]-amino}-methyl)-naphthalen-2-yloxy]-acetic acid
[0197] Step 1:
[1-Bromo-6-({[1-(4-chloro-phenyl)-5-trifluoromethyl-1H-pyra-
zole-4-carbonyl]-amino}-methyl)-naphthalen-2-yloxy]-acetic acid
methyl ester. In the same manner as described in step 4 of Example
15
[1-bromo-6-({[1-(4-chloro-phenyl)-5-trifluoromethyl-1H-pyrazole-4-carbony-
l]-amino}-methyl)-naphthalen-2-yloxy]-acetic acid methyl ester
(0.25 g, 61%) was isolated as an off-white solid, mp
206-207.degree. C.
[0198] Elemental Analysis for
C.sub.25H.sub.18BrClF.sub.3N.sub.3O.sub.4 Calc'd: C, 50.32; H,
3.04; N, 7.04 Found: C, 50.30; H, 2.76; N, 6.74
[0199] Step 2:
[1-Bromo-6-({[1-(4-chloro-phenyl)-5-trifluoromethyl-1H-pyra-
zole-4-carbonyl]-amino}-methyl)-naphthalen-2-yloxy]-acetic acid. A
mixture of
[1-bromo-6-({[1-(4-chloro-phenyl)-5-trifluoromethyl-1H-pyrazole-4-carb-
onyl]-amino}-methyl)-naphthalen-2-yloxy]-acetic acid methyl ester
(0.175 g, 0.29 mmol), prepared in the previous step, 1N NaOH (323
.mu.L, 0.323 mmol), 2 mL of H.sub.2O and 100 mL of methanol was
warmed until all solids had gone into solution. When the reaction
cooled a solid precipitated. After the reaction had stirred for 17
h (overnight) a solid was still present. Another 162 .mu.L (0.162
mmol) of 1N NaOH was added. The reaction stirred for 18 h. The
reaction was filtered to remove any trace particles and acidified
with 1N HCl until pH 1 by litmus paper. The methanol was removed
under reduced pressure. The solid formed was collected by
filtration and dried under reduced pressure to give the title
compound (0.14 g, 8.3%) as a white solid, mp 245.degree. C.
[0200] Elemental Analysis for
C.sub.24H.sub.16ClBrF.sub.3N.sub.3O.sub.4+0.- 29 mol H.sub.2O
Calc'd: C, 49.03; H, 2.84; N, 7.15 Found: C, 48.85; H, 2.48; N,
7.23
EXAMPLE 17
2-Butyl-benzofuran-3-carboxylic acid
[5-bromo-6-(1H-tetrazol-5-ylmethoxy)-- naphthalen-2-ylmethyl]-amide
sodium salt
[0201] Step 1: 2-Butyl-benzofuran-3-carboxylic acid
(5-bromo-6-hydroxy-naphthalen-2-ylmethyl)-amide. Bromine (210
.mu.L, 4.02 mmol) in 50 mL of glacial HOAc was added under nitrogen
dropwise over 2 h to a solution of 2-butyl-benzofuran-3-carboxylic
acid (6-hydroxy-naphthalen-2-ylmethyl)-amide (1.5 g, 4.02 mmol),
prepared in step 2 of Example 8, in 300 mL of glacial HOAc at room
temperature. After the addition the reaction was stirred at room
temperature for 20 h (overnight). The solid formed was collected by
filtration and dried under reduced pressure to give
2-butyl-benzofuran-3-carboxylic acid
(5-bromo-6-hydroxy-naphthalen-2-ylmethyl)-amide (1.41 g, 81%) as a
light gray solid, mp 192-193.degree. C.
[0202] Elemental Analysis for C.sub.24H.sub.22BrNO.sub.3 Calc'd: C,
63.73; H, 4.90; N, 3.10 Found: C, 62.59; H, 4.74; N, 3.00
[0203] Step 2: 2-Butyl-benzofuran-3-carboxylic acid
(5-bromo-6-cyanomethoxy-naphthalen-2-ylmethyl)-amide. A mixture of
2-butyl-benzofuran-3-carboxylic acid
(5-bromo-6-hydroxy-naphthalen-2-ylme- thyl)-amide (300 mg, 0.66
mmol), prepared in the previous step, bromoacetonitrile (56 .mu.L,
0.80 mmol) and potassium carbonate (460 mg, 3.32 mmol) in 15 mL of
DMF was stirred under nitrogen at room temperature for 18 h
(overnight). The reaction was diluted with ethyl acetate, extracted
multiple times with water, dried (MgSO.sub.4) and the solvent
removed under reduced pressure to give
2-butyl-benzofuran-3-carboxylic acid
(5-bromo-6-cyanomethoxy-naphthalen-2-ylmethyl)-amide (324 mg, 99%)
as an off-white solid, mp154-157.degree. C.
[0204] Elemental Analysis for C.sub.26H.sub.23BrN.sub.2O.sub.3
Calc'd: C, 63.55; H, 4.72; N, 5.70 Found: C, 62.95; H, 4.57; N,
5.86
[0205] Step 3: 2-Butyl-benzofuran-3-carboxylic acid
[5-bromo-6-(1H-tetrazol-5-ylmethoxy)-naphthalen-2-ylmethyl]-amide
sodium salt. A mixture of 2-butyl-benzofuran-3-carboxylic acid
(5-bromo-6-cyanomethoxy-naphthalen-2-ylmethyl)-amide (200 mg, 0.41
mmol), prepared in the previous step, sodium azide (80 mg, 1.22
mmol) and ammonium chloride (65 mg, 1.22 mmol) in 10 mL of DMF was
stirred under nitrogen at 100.degree. C. for 4 h. By TLC starting
material remained. An additional 80 mg of sodium azide and 65 mg of
ammonium chloride were added and the reaction stirred at
100.degree. C. for 4 h. The reaction was diluted with ethyl
acetate, made basic by the addition of 1 N NaOH and partitioned
with water. The organic layer was separated and the aqueous layer
extracted three times with ethyl acetate. By TLC most of the
material was in the ethyl acetate extracts. The extracts were
washed multiple times with water, dried (MgSO.sub.4) and the
solvent removed under reduced pressure to give the title compound
(143 mg, 61%) as an off-white solid, mp 214-215.degree. C.
[0206] Elemental Analysis for C.sub.26H.sub.24BrN5O.sub.3Na+0.52
H.sub.2O Calc'd: C, 55.20; H, 4.28; N, 12.38 Found: C, 56.62; H,
4.65; N, 12.71
EXAMPLE 18
2-(1-Bromo-6-{[(2-butyl-benzofuran-3-carbonyl)-amino]-methyl}-naphthalen-2-
-yloxy)-3-phenyl-propionic acid
[0207] Step 1:
2-(1-Bromo-6-{[(2-butyl-benzofuran-3-carbonyl)-amino]-methy-
l}-naphthalen-2-yloxy)-3-phenyl-propionic acid methyl ester.
2-Hydroxy-3-phenyl-propionic acid methyl ester (200 mg, 1.1 mmol),
prepared in step 1 of Example 7, in 5 mL of anhydrous THF was added
under nitrogen to a solution of 2-butyl-benzofuran-3-carboxylic
acid (5-bromo-6-hydroxy-naphthalen-2-ylmethyl)-amide (500 mg, 1.1
mmol), prepared in step 1 of Example 17, in 5 mL of anhydrous THF
at room temperature. Triphenylphosphine (433 mg, 1.65 mmol) was
then added. Diethyl azodicarboxylate (260 .mu.L, 1.65 mmol) in 5 mL
of anhydrous THF was added to the mixture at ice-bath temperature
dropwise over 5 minutes. After the addition the reaction was
stirred at ice-bath temperature for 15 minutes and then at room
temperature for 17 h. The solvent was removed under reduced
pressure and the residue partitioned between ethyl acetate and
water. The organic layer was separated and the aqueous layer
extracted three times with ethyl acetate. The combined extracts
were dried (MgSO.sub.4) and the solvent removed under reduced
pressure to give 1.36 g of an off-white solid. Purification of the
solid by chromatography on silica gel using methylene chloride as
the eluent gave
2-(1-bromo-6-{[(2-butyl-benzofuran-3-carbonyl)-amino]-methyl}-naphthalen--
2-yloxy)-3-phenyl-propionic acid methyl ester as a white solid, mp
110-112.degree. C.
[0208] Elemental Analysis for C.sub.34H.sub.32BrNO.sub.5 Calc'd: C,
66.45; H, 5.25; N, 2.28 Found: C, 66.19; H, 5.01; N, 2.19
[0209] Step 2:
2-(1-Bromo-6-{[(2-butyl-benzofuran-3-carbonyl)-amino]-methy-
l}-naphthalen-2-yloxy)-3-phenyl-propionic acid. 1 N Sodium
hydroxide (220 .mu.L, 0.22 mmol) was added under nitrogen to a
solution of
2-(1-bromo-6-{[(2-butyl-benzofuran-3-carbonyl)-amino]-methyl}-naphthalen--
2-yloxy)-3-phenyl-propionic acid methyl ester (107 mg, 0.17 mmol),
prepared in the previous step, in 40 mL of methanol plus 10 mL of
water at room temperature. After the addition the reaction was
stirred at room temperature overnight. By TLC starting material
remained. Additional quantities of 1 N NaOH were added until the
reaction was complete by TLC. The reaction was acidified by the
addition of 1 N HCl and then concentrated under reduced pressure to
remove the methanol. The solid formed was collected by filtration
and dried under reduced pressure to give the title compound (61 mg,
58%) as a white solid, mp 125-130.degree. C.
[0210] Elemental Analysis for C.sub.33H.sub.30BrNO.sub.5+0.25
H.sub.2O Calc'd: C, 65.51; H, 5.08; N, 2.32 Found: C, 65.51; H,
4.97; N, 2.22
EXAMPLE 19
Sodium;
(1-bromo-6-{[(2-butyl-benzofuran-3-carbonyl)-amino]-methyl}-naphth-
alen-2-yloxy)-acetate
[0211] Step 1:
(1-Bromo-6-{[(2-butyl-benzofuran-3-carbonyl)-amino]-methyl}-
-naphthalen-2-yloxy)-acetic acid methyl ester. A mixture of
2-butyl-benzofuran-3-carboxylic acid
(5-bromo-6-hydroxy-naphthalen-2-ylme- thyl)-amide (450 mg, 0.99
mmol), prepared in step 2 of Example 17, methyl bromoacetate (90
.mu.L, 0.99 mmol) and potassium carbonate (690 mg, 5 mmol) in 10 mL
of DMF was stirred under nitrogen at room temperature overnight.
The reaction was diluted with ethyl acetate, extracted multiple
times with water, dried (MgSO.sub.4) and the solvent removed under
reduced pressure to give 472 mg of a yellow solid.
Recrystallization of the solid from isopropyl alcohol gave
(1-bromo-6-{[(2-butyl-benzofuran-3-carbonyl)-amino]-methyl}-naphthalen-2--
yloxy)-acetic acid methyl ester (352 mg, 68%) as an off-white
solid, mp 140-141.degree. C.
[0212] Elemental Analysis for C.sub.27H.sub.26BrNO.sub.5 Calc'd: C,
61.84; H, 5.00; N, 2.67 Found: C, 61.34; H, 4.79; N, 2.63
[0213] Step 2: Sodium;
(1-bromo-6-{[(2-butyl-benzofuran-3-carbonyl)-amino]-
-methyl}-naphthalen-2-yloxy)-acetate. 1 N NaOH (477 .mu.L, 0.477
mmol) was added to a solution of
(1-bromo-6-{[(2-butyl-benzofuran-3-carbonyl)-amino-
]-methyl}-naphthalen-2-yloxy)-acetic acid methyl ester (250 mg,
0.477 mmol), prepared in the previous step, in 30 mL of THF plus 15
mL of water at room temperature. After the addition the reaction
was stirred at room temperature overnight. The solvent was removed
under reduced pressure to give the title compound (200 mg, 75%) as
a white solid, mp 260.degree. C.
[0214] Elemental Analysis for
C.sub.26H.sub.23BrNO.sub.5Na+1.4H.sub.2O Calc'd: C, 56.01; H, 4.66;
N, 2.51 Found: C, 55.63; N, 4.66; N, 2.47
EXAMPLE 20
2-Methyl-benzofuran-3-carboxylic acid
[5-bromo-6-(1H-tetrazol-5-ylmethoxy)-
-naphthalen-2-ylmethyl]-amide
[0215] Step 1: 2-Methyl-benzofuran-3-carboxylic acid. In the same
manner as described in step 1 of Example 3,
2-methyl-benzofuran-3-carboxylic acid (4.24 g, 34%) was isolated as
a yellow solid, mp 171-176.degree. C.
[0216] Elemental Analysis for C.sub.10H.sub.8.sub.3 Calc'd: C,
68.18; H, 4.58; N, 0.00 Found: C, 67.50; H, 4.43; N, 0.22
[0217] Step 2: 2-Methyl-benzofuran-3-carbonyl chloride. In the same
manner as described in step 2 of Example 3,
2-methyl-benzofuran-3-carbonyl chloride was isolated as a dark
brown solid. Without additional purification it was immediately
used in step 3.
[0218] Step 3: 2-Methyl-benzofuran-3-carboxylic acid
(6-hydroxy-naphthalen-2-ylmethyl)-amide.
2-Methyl-benzofuran-3-carbonyl chloride, prepared in the previous
step, in 50 mL of anhydrous THF was added under nitrogen dropwise
over 1.5 h to a solution of 6-aminomethyl-naphthalen-2-ol (1.00 g,
5.79 mmol), prepared in step 1 of Example 8, and triethylamine (811
.mu.L, 5.82 mmol) in 300 mL of anhydrous THF at room temperature.
After the addition the reaction was stirred at room temperature for
19 h (overnight). The solvent was removed under reduced pressure.
The dark brown residue was partitioned between 400 mL of 20% MeOH
in methylene chloride and 1 N HCl. After separating the organic
layer, the aqueous layer was extracted three times with 20% MeOH in
methylene chloride. The combined extracts were dried (MgSO.sub.4)
and the solvent removed under reduced pressure to give 1.59 g of a
brown solid. The solid was taken up in 50 mL of boiling ethyl
acetate, filtered, concentrated to a volume of 25 mL and diluted
with 75 mL of hexane. The solid formed was collected by filtration
and dried under reduced pressure to give
2-methyl-benzofuran-3-carboxylic acid
(6-hydroxy-naphthalen-2-ylmethyl)-amide (606 mg, 32%) as a brown
solid, mp 195-198.degree. C.
[0219] Elemental Analysis for C.sub.21H.sub.17NO.sub.3 Calc'd: C,
76.12; H, 5.17; N, 4.23 Found: C, 74.62; H, 4.95; N, 3.84
[0220] Step 4: 2-Methyl-benzofuran-3-carboxylic acid
(5-bromo-6-hydroxy-naphthalen-2-ylmethyl)-amide. Bromine (83 .mu.L,
1.61 mmol) in 15 mL of glacial HOAc was added under nitrogen
dropwise over 3 h to a solution of 2-methyl-benzofuran-3-carboxylic
acid (6-hydroxy-naphthalen-2-ylmethyl)-amide (537 mg, 1.62 mmol),
prepared in the previous step, in 60 mL of glacial HOAc at room
temperature. After the addition the reaction was stirred at room
temperature for 1 h. The solvent was removed under reduced pressure
and the residue partitioned between 20% MeOH in methylene chloride
and 5% NaHCO.sub.3. After separating the organic layer the aqueous
layer was extracted three times with 20% MeOH in methylene
chloride. The combined extracts were dried (MgSO.sub.4) and the
solvent removed under reduced pressure to give
2-methyl-benzofuran-3-carboxylic acid
(5-bromo-6-hydroxy-naphthalen-2-ylm- ethyl)-amide (690 mg, 100%) as
a brown solid, mp 179-181.degree. C.
[0221] Elemental Analysis for C.sub.21H.sub.16BrNO.sub.3 Calc'd: C,
61.48; H, 3.93; N, 3.41 Found: C, 57.06; H, 3.78; N, 3.07
[0222] Step 5: 2-Methyl-benzofuran-3-carboxylic acid
(5-bromo-6-cyanomethoxy-naphthalen-2-ylmethyl)-amide. A mixture of
2-methyl-benzofuran-3-carboxylic acid
(5-bromo-6-hydroxy-naphthalen-2-ylm- ethyl)-amide (401 mg, 0.98
mmol), prepared in the previous step, bromoacetonitrile (82 .mu.L,
1.18 mmol) and potassium carbonate (674 mg, 4.88 mmol) in 20 mL of
DMF was stirred under nitrogen at room temperature for 12 h
(overnight). The reaction was partitioned between ethyl acetate and
water. The organic layer was separated, extracted multiple times
with water, dried (MgSO.sub.4) and the solvent removed under
reduced pressure to give 386 mg of a brown solid. Purification of
the solid on 100 g of silica gel (230-400 mesh) using 1% to 4%
ethyl acetate in methylene chloride as the eluent gave
2-methyl-benzofuran-3-carboxylic acid
(5-bromo-6-cyanomethoxy-naphthalen-2-ylmethyl)-amide (330 mg, 75%)
as a light yellow solid, mp 180-182.degree. C.
[0223] Elemental Analysis for C.sub.23H.sub.7BrN.sub.2O.sub.3
Calc'd: C, 61.48; H, 3.81; N, 6.23 Found: C, 60.09; H, 3.63; N,
6.09
[0224] Step 6: 2-Methyl-benzofuran-3-carboxylic acid
[5-bromo-6-(1H-tetrazol-5-ylmethoxy)-naphthalen-2-ylmethyl]-amide.
A mixture of 2-methyl-benzofuran-3-carboxylic acid
(5-bromo-6-cyanomethoxy-- naphthalen-2-ylmethyl)-amide (233 mg,
0.52 mmol), prepared in the previous step, sodium azide (101 mg,
1.56 mmol) and ammonium chloride (83 mg, 1.55 mmol) in 15 mL of DMF
was stirred under nitrogen at 100.degree. C. for 8 h. The reaction
was diluted with 35 mL of water, made basic by the addition of 3 mL
of 1 N NaOH and extracted five times with ethyl acetate. The
aqueous layer was acidified by the addition of 5 mL of 1 N HCl. The
solid that precipitated was collected by filtration and dried under
reduced pressure to give the title compound (216 mg, 85%) as a
white solid, mp 242-244.degree. C.
[0225] Elemental Analysis for C.sub.23H.sub.18BrN.sub.5O.sub.3+0.09
H.sub.2O Calc'd: C, 55.93; H, 3.71; N, 14.18 Found: C, 55.66; H,
3.54; N, 13.99
EXAMPLE 21
2-Ethyl-benzofuran-3-carboxylic acid [5-bromo-6-(1H-tetrazol-5-yl
methoxy)-naphthalen-2-yl methyl]-amide
[0226] Step 1: 2-Ethyl-benzofuran-3-carboxylic acid. In the same
manner as described in step 1 of Example 3,
2-ethyl-benzofuran-3-carboxylic acid (11.69 g, 54%) was isolated as
a brown solid, mp 102-106.degree. C.
[0227] Elemental Analysis for C.sub.11H.sub.10O.sub.3 Calc'd: C,
69.46; H, 5.30; N, 0.00 Found: C, 69.20; H, 5.13; N, -0.16
[0228] Step 2: 2-Ethyl-benzofuran-3-carbonyl chloride. In the same
manner as described in step 2 of Example 3,
2-ethyl-benzofuran-3-carbonyl chloride was isolated as a brown oil.
Without additional purification it was immediately used in step
3.
[0229] Step 3: 2-Ethyl-benzofuran-3-carboxylic acid
(6-hydroxy-naphthalen-2-ylmethyl)-amide. In the same manner as
described in step 3 of Example 20, 2-ethyl-benzofuran-3-carboxylic
acid (6-hydroxy-naphthalen-2-ylmethyl)-amide (899 mg, 45%) was
isolated as a light brown solid, mp 203-205.degree. C.
[0230] Elemental Analysis for C.sub.22H.sub.19NO.sub.3 Calc'd: C,
76.50; H, 5.54; N, 4.06 Found: C, 75.83; H, 5.61; N, 4.04
[0231] Step 4: 2-Ethyl-benzofuran-3-carboxylic acid
(5-bromo-6-hydroxy-naphthalen-2-ylmethyl)-amide. In the same manner
as described in step 4 of Example 20,
2-ethyl-benzofuran-3-carboxylic acid
(5-bromo-6-hydroxy-naphthalen-2-ylmethyl)-amide (365 mg, 31%) was
isolated, after recrystallization from ethyl acetate, as a light
brown solid, mp 188-190.degree. C.
[0232] Elemental Analysis for C.sub.22H.sub.18BrNO.sub.3 Calc'd: C,
62.28; H, 4.28; H, 3.30 Found: C, 61.75; H, 3.91; N, 3.25
[0233] Step 5: 2-Ethyl-benzofuran-3-carboxylic acid
(5-bromo-6-cyanomethoxy-naphthalen-2-ylmethyl)-amide. In the same
manner as described in step 5 of Example 20,
2-ethyl-benzofuran-3-carboxylic acid
(5-bromo-6-cyanomethoxy-naphthalen-2-ylmethyl)-amide (328 mg, 100%)
was isolated as a tan solid, mp 181-183.degree. C.
[0234] Elemental Analysis for C.sub.24H.sub.19BrN.sub.2O.sub.3
Calc'd: C, 62.22; H, 4.13; N, 6.05 Found: C, 61.30; H, 3.97; N,
5.92
[0235] Step 6: 2-Ethyl-benzofuran-3-carboxylic acid
[5-bromo-6-(1H-tetrazol-5-ylmethoxy)-naphthalen-2-ylmethyl]-amide.
In the same manner as described in step 6 of Example 20, the title
compound was isolated as an off-white solid, mp 235-238.degree.
C.
[0236] Elemental Analysis for C.sub.24H.sub.20BrN.sub.5O.sub.3
Calc'd: C, 56.85; H, 3.99; N, 13.81 Found: C, 56.45; H, 3.74; N,
13.73
EXAMPLE 22
1-Phenyl-5-propyl-1H-pyrazole-4-carboxylic acid
[5-bromo-6-(1H-tetrazol-5--
ylmethoxy)-naphthalen-2-ylmethyl]-amide
[0237] Step 1: 1-Phenyl-5-propyl-1H-pyrazole-4-carboxylic acid
(6-hydroxy-naphthalen-2-ylmethyl)-amide. A solution of
1-phenyl-5-propyl-1H-pyrazole-4-carbonyl chloride (2.0 g, 8 mmol)
in 20 mL of methylene chloride was added dropwise under nitrogen to
a mixture of 6-aminomethyl-naphthalen-2-ol (1.63 g, 9.42 mmol),
prepared in step 1 of Example 8, and 75 mL of anhydrous pyridine.
The reaction stirred at room temperature for 17 h (overnight). The
reaction was diluted with methylene chloride and extracted with 1 N
HCl. The aqueous layer was separated and extracted with methylene
chloride. The organic extracts were combined, dried (MgSO.sub.4)
and the solvent removed under reduced pressure to give a brown
solid. The solid was recrystallized from ethyl acetate and then
again from isopropanol. The crystals were collected by filtration
and dried under reduced pressure to give
1-phenyl-5-propyl-1H-pyrazole-4-carboxylic acid
(6-hydroxy-naphthalen-2-y- lmethyl)-amide (0.767 g, 25%) as a tan
solid, mp 189-190.degree. C.
[0238] Elemental Analysis for C.sub.24H.sub.23N.sub.3O.sub.2
Calc'd: C, 74.78; H, 6.01; N, 10.90 Found: C, 73.64; H, 5.78; N,
10.77
[0239] Step 2:
4-[(5-Bromo-6-hydroxy-naphthalen-2-ylmethyl)-carbamoyl]-2-p-
henyl-3-propyl-2H-pyrazol-1-ium; bromide. A solution of bromine
(0.05 mL, 0.978 mmol) in 25 mL of glacial acetic acid was added
dropwise under nitrogen over 2 h to a solution of
1-phenyl-5-propyl-1H-pyrazole-4-carbox- ylic acid
(6-hydroxy-naphthalen-2-ylmethyl)-amide (0.377 g, 0.978 mmol),
prepared in the previous step, in 100 mL of glacial acetic acid.
The reaction stirred for 17 h (overnight). An orange solid, which
precipitated from solution, was collected by filtration and rinsed
with glacial acetic acid. The solid was dried under reduced
pressure to give
4-[(5-bromo-6-hydroxy-naphthalen-2-ylmethyl)-carbamoyl]-2-phenyl-3-propyl-
-2H-pyrazol-1-ium; bromide (0.4431 g, 82%) as a light brown solid,
mp 198-200.degree. C.
[0240] Elemental Analysis for
C.sub.24H.sub.22BrN.sub.3O.sub.2+HBr+0.25 H.sub.2O Calc'd: C,
52.43; H, 4.31; N, 7.64 Found: C, 51.61; H, 4.04; N, 7.42
[0241] Step 3: 1-Phenyl-5-propyl-1H-pyrazole-4-carboxylic acid
(5-bromo-6-cyanomethoxy-naphthalen-2-ylmethyl)-amide. A mixture of
4-[(5-bromo-6-hydroxy-naphthalen-2-ylmethyl)-carbamoyl]-2-phenyl-3-propyl-
-2H-pyrazol-1-ium; bromide (0.30 g, 0.646 mmol), prepared in the
previous step, bromoacetonitrile (0.054 mL, 0.775 mmol), potassium
carbonate (0.446 g, 3.23 mmol) and 10 mL of DMF was stirred under
nitrogen at room temperature overnight. The reaction was diluted
with ethyl acetate and extracted multiple times with water and with
a saturated sodium chloride solution. The organic layer was
separated, dried (MgSO.sub.4), and the solvent removed under
reduced pressure to give a brown oil. The oil was chromatographed
on a 90 g KP-SIL 60 .DELTA. Biotage column using 15% ethyl acetate
in methylene chloride as the eluent. All fractions containing
product were combined and the solvent removed under reduced
pressure to give 1-phenyl-5-propyl-1H-pyrazole-4-carboxylic acid
(5-bromo-6-cyanomethoxy-naphthalen-2-ylmethyl)-amide (0.196 g, 60%)
as a light yellow solid, mp 175-176.degree. C.
[0242] Elemental Analysis for C.sub.26H.sub.23BrN.sub.4O.sub.2
Calc'd: C, 62.04; H, 4.61; N, 11.13 Found: C, 62.03; H, 4.47; N,
11.00
[0243] Step 4: 1-Phenyl-5-propyl-1H-pyrazole-4-carboxylic acid
[5-bromo-6-(1H-tetrazol-5-ylmethoxy)-naphthalen-2-ylmethyl]-amide.
A mixture of 1-phenyl-5-propyl-1H-pyrazole-4-carboxylic acid
(5-bromo-6-cyanomethoxy-naphthalen-2-ylmethyl)-amide (0.15 g, 0.3
mmol), prepared in the previous step, sodium azide (0.059 g, 0.9
mmol), ammonium chloride (0.048 g, 0.9 mmol) and 10 mL of DMF was
stirred at 100.degree. C. for 1.5 h. By TLC starting material
remained. Additional sodium azide (0.059 g, 0.9 mmol) and ammonium
chloride (0.048 g, 0.9 mmol) were added and the reaction stirred at
100.degree. C. for 2 h. Again by TLC starting material remained.
Additional sodium azide (0.059 g, 0.9 mmol) and ammonium chloride
(0.048 g, 0.9 mmol) were added and the reaction stirred at
100.degree. C. for 5 h. The reaction was diluted with water and
extracted four times with ethyl acetate. The organic layers were
combined and acidified with .about.3 mL 1N HCl. The mixture was
swirled for one minute and then the solution was dried (MgSO.sub.4)
and filtered. The solvent was removed under reduced pressure and
the resulting residue was taken up in 20 mL of water. The solid
that formed was collected by filtration and dried under reduced
pressure to give the title compound (0.107 g, 65%) as a tan solid,
mp 219-220.degree. C.
[0244] Elemental Analysis for C.sub.26H.sub.24BrN.sub.7O.sub.2+0.01
H.sub.2O Calc'd: C, 56.96; H, 4.45; N, 17.88 Found: C, 57.12; H,
4.45; N, 17.61
EXAMPLE 23
2-Butyl-benzofuran-3-carboxylic acid
[6-(1H-tetrazol-5-ylmethoxy)-5-p-toly-
l-naphthalen-2-ylmethyl]-amide
[0245] Step 1: 2-Butyl-benzofuran-3-carboxylic acid
(6-Hydroxy-5-p-tolyl-naphthalen-2-ylmethyl)-amide. A mixture of
2-butyl-benzofuran-3-carboxylic acid
(5-bromo-6-hydroxy-naphthalen-2-ylme- thyl)-amide (759 mg, 1.68
mmol), prepared in step 1 of Example 17, 4-methylphenylboronic acid
(342 mg, 2.52 mmol) and potassium carbonate (471 mg, 3.40 mmol) in
90 mL of dimethoxyethane plus 10 mL of water was heated to
50.degree. C. while being purged with nitrogen. After 30 minutes
dichloro[1,1' bis(diphenylphosphino)ferrocene]palladium (II)
dichloromethane (147 mg, 0.18 mmol) was added and the reaction
heated to 70.degree. C. After 3 h starting material remained. An
additional 349 mg (2.57 mmol) of 4-methylphenylboronic acid and 150
mg (0.18 mmol) of
dichloro[1,1'-bis(diphenylphosphino)ferrocene]palladium (II)
dichloromethane were added and the mixture stirred at 70.degree. C.
for 2 h. This process was repeated until no more starting material
remained. The reaction was concentrated under reduced pressure to
remove the dimethoxyethane and the residue partitioned between
methylene chloride and water. The organic layer was separated,
extracted multiple times with water, dried (MgSO.sub.4) and the
solvent removed under reduced pressure to give 1.297 g of material.
Purification of the material on a 90 g KP-SIL 60 .DELTA. Biotage
column using methylene chloride as the eluent gave
2-butyl-benzofuran-3-carboxylic acid
(6-hydroxy-5-p-tolyl-naphthalen- -2-ylmethyl)-amide (521 mg, 67%)
as a white solid, mp 103-105.degree. C.
[0246] Elemental Analysis for C.sub.31H.sub.29NO.sub.3 Calc'd: C,
80.32; H, 6.31; N, 3.02 Found: C, 79.81; H, 6.09; N, 2.88
[0247] Step 2: 2-Butyl-benzofuran-3-carboxylic acid
(6-cyanomethoxy-5-p-tolyl-naphthalen-2-ylmethyl)-amide. A mixture
of 2-butyl-benzofuran-3-carboxylic acid
(6-hydroxy-5-p-tolyl-naphthalen-2-yl- methyl)-amide (252 mg, 0.54
mmol), prepared in the previous step, bromoacetonitrile (55 .mu.L,
0.81 mmol) and potassium carbonate (378 mg, 2.73 mmol) in 15 mL of
DMF was stirred under nitrogen at room temperature for 19 h
(overnight). The reaction was diluted with ethyl acetate, extracted
multiple times with water, dried (MgSO.sub.4) and the solvent
removed under reduced presure to give
2-butyl-benzofuran-3-carboxylic acid
(6-cyanomethoxy-5-p-tolyl-naphthalen-2-ylmethyl)-amide (269 mg,
99%) as a light brown solid, mp 114-117.degree. C.
[0248] Elemental Analysis for C.sub.33H.sub.30N.sub.2O.sub.3
Calc'd: C, 78.86; H, 6.02; N, 5.57 Found: C, 77.91; H, 6.08; N,
5.45
[0249] Step 3: 2-Butyl-benzofuran-3-carboxylic acid
[6-(1H-tetrazol-5-ylmethoxy)-5-p-tolyl-naphthalen-2-ylmethyl]-amide.
A mixture of 2-butyl-benzofuran-3-carboxylic acid
(6-cyanomethoxy-5-p-tolyl- -naphthalen-2-ylmethyl)-amide (182 mg,
0.36 mmol), prepared in the previous step, sodium azide (77.6 mg,
1.19 mmol) and ammonium chloride (102 mg, 1.90 mmol) in 10 mL of
DMF was stirred under nitrogen at 100.degree. C. for 21 h
(overnight). If starting material remains additional sodium azide
and ammonium chloride are added and the stirring continued at
100.degree. C. until the reaction is complete. The reaction was
diluted with water, made basic by the addition of 1 N NaQH and
extracted multiple times with ethyl acetate. The ethyl acetate
extracts were combined, acidified with 1 N HCl and then
concentrated under reduced pressure. The solid present was
collected by filtration and dried under reduced pressure to give
the title compound (130 mg, 66%) as a white solid, mp
162-166.degree. C.
[0250] Elemental Analysis for C.sub.33H.sub.31N.sub.5O.sub.3+0.03
H.sub.2O Calc'd: C, 72.57; H, 5.73; N, 12.82 Found: C, 72.19; H,
5.66; N, 12.54
EXAMPLE 24
2-Butyl-benzofuran-3-carboxylic acid
[5-phenyl-6-(1H-tetrazol-5-ylmethoxy)-
-naphthalen-2-ylmethyl]-amide
[0251] Step 1: 2-Butyl-benzofuran-3-carboxylic acid
(6-hydroxy-5-phenyl-naphthalen-2-ylmethyl)-amide. In the same
manner as described in step 1 of Example 23,
2-butyl-benzofuran-3-carboxylic acid
(6-hydroxy-5-phenyl-naphthalen-2-ylmethyl)-amide (532 mg, 54%) was
obtained as a white solid, mp 72-72.degree. C.
[0252] Elemental Analysis for C.sub.30H.sub.27NO.sub.3 Calc'd: C,
80.15; H, 6.05; N, 3.12 Found: C, 79.00; H, 6.40; N, 2.92
[0253] Step 2: 2-Butyl-benzofuran-3-carboxylic acid
(6-cyanomethoxy-5-phenyl-naphthalen-2-ylmethyl)-amide. A mixture of
2-butyl-benzofuran-3-carboxylic acid
(6-hydroxy-5-phenyl-naphthalen-2-ylm- ethyl)-amide (366 mg, 0.813
mmol), prepared in the previous step, bromoacetonitrile (68 .mu.L,
0.976 mmol) and potassium carbonate (562 mg, 4.07 mmol) in 20 mL of
DMF was stirred under nitrogen at room temperature for 23 h
(overnight). The reaction was diluted with ethyl acetate, extracted
multiple times with water, dried (MgSO.sub.4) and the solvent
removed under reduced pressure to give a brown solid. Purification
of the solid on 20 g of silica gel (230-400 mesh) using
hexane-ethyl acetate as the eluent gave
2-butyl-benzofuran-3-carboxylic acid
(6-cyanomethoxy-5-phenyl-naphthalen-2-ylmethyl)-amide (342 mg, 86%)
as a light brown solid, mp 135-138.degree. C.
[0254] Elemental analysis for C.sub.32H.sub.28N.sub.2O.sub.3
Calc'd: C, 78.67; H, 5.78; N, 5.73 Found: C, 77.54; H, 5.98; N,
5.63
[0255] Step 3: 2-Butyl-benzofuran-3-carboxylic acid
[5-phenyl-6-(1H-tetrazol-5-ylmethoxy)-naphthalen-2-ylmethyl]-amide.
In the same manner as described in step 3 of Example 23, the title
compound (124 mg, 46%) was isolated as a white solid, mp
192-196.degree. C.
[0256] Elemental Analysis for
C.sub.32H.sub.29N.sub.5O.sub.3.0,1H.sub.2O Calc'd: C, 72.05; H,
5.52; N, 13.13 Found: C, 71.63; H, 5.54; N, 12.76
EXAMPLE 25
2-Butyl-benzofuran-3-carboxylic [5-(4-methoxy
phenyl)-6-(1H-tetrazol-5-ylm- ethoxy)-naphthalen-2-ylmethyl]-amide,
sodium salt
[0257] Step 1: 2-Butyl-benzofuran-3-carboxylic acid
[6-hydroxy-5-(4-methoxy-phenyl)-naphthalen-2-ylmethyl]-amide. In
the same manner as described in step 1 of Example 23,
2-butyl-benzofuran-3-carboxy- lic acid
[6-hydroxy-5-(4-methoxy-phenyl)-naphthalen-2-ylmethyl]-amide (529
mg, 50%) was obtained as a white solid, mp 118-122.degree. C.
[0258] Elemental Analysis for C.sub.31H.sub.29NO.sub.4 Calc'd: C,
77.64; H, 6.10; N, 2.92 Found: C, 77.18; H, 6.11; N, 2.76
[0259] Step 2: 2-Butyl-benzofuran-3-carboxylic acid
[6-cyanomethoxy-5-(4-methoxy-phenyl)-naphthalen-2-ylmethyl]-amide.
A mixture of 2-butyl-benzofuran-3-carboxylic acid
[6-hydroxy-5-(4-methoxy-p- henyl)-naphthalen-2-ylmethyl]-amide (301
mg, 0.63 mmol), prepared in the previous step, bromoacetonitrile
(52 .mu.L, 0.75 mmol) and potassium carbonate (434 mg, 3.14 mmol)
in 20 mL of DMF was stirred under nitrogen at room temperature for
21 h (overnight). The reaction was diluted with ethyl acetate,
extracted multiple times with water, dried (MgSO.sub.4) and the
solvent removed under reduced pressure to give
2-butyl-benzofuran-3-carboxylic acid
[6-cyanomethoxy-5-(4-methoxy-phenyl)- -naphthalen-2-ylmethyl]-amide
(325 mg, 99%) as a brown solid, mp 139-142.degree. C.
[0260] Elemental Analysis for C.sub.33H.sub.30N.sub.2O.sub.4
Calc'd: C, 76.43; H, 5.83; N, 5.40 Found: C, 75.34; H, 5.76; N,
5.86
[0261] Step 3: 2-Butyl-benzofuran-3-carboxylic [5-(4-methoxy
phenyl)-6-(1H-tetrazol-5-ylmethoxy)-naphthalen-2-ylmethyl]-amide,
sodium salt. A mixture of 2-butyl-benzofuran-3-carboxylic acid
[6-cyanomethoxy-5-(4-methoxy-phenyl)-naphthalen-2-ylmethyl]-amide
(207 mg, 0.40 mmol), prepared in the previous step, sodium azide
(81 mg, 1.25 mmol) and ammonium chloride (63.5 mg, 1.19 mmol) in 10
mL of DMF was stirred under nitrogen at 100.degree. C. for 6.5 h.
If starting material remains additional sodium azide and ammonium
chloride are added and the stirring continued at 100.degree. C.
until the reaction is complete. The reaction was diluted with 75 mL
of water. The solid that formed was collected by filtration and
dried under reduced pressure to give the title compound (116 mg,
51%) as an off-white solid, mp 147-152.degree. C.
[0262] Elemental Analysis for C.sub.33H.sub.31N.sub.5O.sub.4Na+0.71
H.sub.2O Calc'd: C, 66.46; H, 5.31; N, 11.74 Found: C, 67.86; H,
5.50; N, 12.08
EXAMPLE 26
2-Butyl-benzofuran-3-carboxylic acid
[5-(4-chloro-phenyl)-6-(1-tetrazol-5--
ylmethoxy)-naphthalen-2-ylmethyl]-amide.
[0263] Step 1: 2-Butyl-benzofuran-3-carboxylic acid
[5-(4-chloro-phenyl)-6-hydroxy-naphthalen-2-ylmethyl]-amide. In the
same manner as described in step 1 of Example 23,
2-butyl-benzofuran-3-carboxy- lic acid
[5-(4-chloro-phenyl)-6-hydroxy-naphthalen-2-ylmethyl]-amide (556
mg, 52%) was obtained as a white solid, mp 122-124.degree. C.
[0264] Elemental Analysis for C.sub.30H.sub.26ClNO.sub.3 Calc'd: C,
74.45; H, 5.41; N, 2.89 Found: C, 74.25; H, 5.32; N, 2.89
[0265] Step 2: 2-Butyl-benzofuran-3-carboxylic acid
[5-(4-chloro-phenyl)-6-cyanomethoxy-naphthalen-2-ylmethyl]-amide. A
mixture of 2-butyl-benzofuran-3-carboxylic acid
[5-(4-chloro-phenyl)-6-hy- droxy-naphthalen-2-ylmethyl]-amide (258
mg, 0.53 mmol), prepared in the previous step, bromoacetonitrile
(44 .mu.L, 0.63 mmol) and potassium carbonate (362 mg, 2.62 mmol)
in 20 mL of DMF was stirred under nitrogen at room temperature for
for 48 h. By TLC starting material remained. Additional 20 .mu.L
aliquots of bromoacetonitrile were added until the reaction was
complete. The reaction was diluted with ethyl acetate, extracted
multiple times with water, dried (MgSO.sub.4) and the solvent
removed under reduced pressure to give 257 mg of a brown solid.
Purification of the solid on a 90 g KP-SIL 60 .DELTA. Biotage
column using methylene chloride as the eluent produce a solid
material which was recrystallized from isopropyl alcohol to give
2-butyl-benzofuran-3-carbox- ylic acid
[5-(4-chloro-phenyl)-6-cyanomethoxy-naphthalen-2-ylmethyl]-amide
(101 mg, 36%) as a white solid, mp 154-158.degree. C.
[0266] Elemental Analysis for C.sub.32H.sub.27ClN.sub.2O.sub.3
Calc'd: C, 73.49; H, 5.20; N, 5.36 Found: C, 73.42; H, 5.09; N,
5.31
[0267] Step 3: 2-Butyl-benzofuran-3-carboxylic acid
[5-(4-chloro-phenyl)-6-(1H-tetrazol-5-ylmethoxy)-naphthalen-2-ylmethyl]-a-
mide. A mixture of 2-butyl-benzofuran-3-carboxylic acid
[5-(4-chloro-phenyl)-6-cyanomethoxy-naphthalen-2-ylmethyl]-amide
(152 mg, 0.29 mmol), prepared in the previous step, sodium azide
(59 mg, 0.90 mmol) and ammonium chloride (85 mg, 1.58 mmol) in 10
mL of DMF was stirred under nitrogen at 100.degree. C. for 24 h
(overnight). If starting material remains additional sodium azide
and ammonium chloride are added and the stirring continued at
100.degree. C. until the reaction is complete. The reaction was
diluted with 50 mL of water, made basic by the addition of 1 N NaOH
and extracted multiple times with ethyl acetate. The aqueous layer
was acidified. The solid that formed was collected by filtration
and dried under reduced pressure to give the title compound (149
mg, 91%) as a white solid, mp 208-211.degree. C.
[0268] Elemental Analysis for C.sub.32H.sub.28ClN.sub.5O.sub.3+0.19
H.sub.2O Calc'd: C, 67.49; H, 5.02; N, 12.30 Found: C, 67.90; H,
4.99; N, 12.37
EXAMPLE 27
2-Butyl-benzofuran-3-carboxylic acid
[5-(4-tert-butyl-phenyl)-6-(1H-tetraz-
ol-5-ylmethoxy)-naphthalen-2-ylmethyl]-amide
[0269] Step 1: 2-Butyl-benzofuran-3-carboxylic acid
[5-(4-tert-butyl-phenyl)-6-hydroxy-naphthalen-2-ylmethyl]-amide. In
the same manner as described in step 1 of Example 23,
2-butyl-benzofuran-3-ca- rboxylic acid
[5-(4-tert-butyl-phenyl)-6-hydroxy-naphthalen-2-ylmethyl]-am- ide
(525 mg, 47%) was obtained as a white solid, mp 195-197.degree.
C.
[0270] Elemental Analysis for C.sub.34H.sub.35NO.sub.3 Calc'd: C,
80.76; H, 6.98; N, 2.77 Found: C, 80.26; H, 7.15; N, 2.78
[0271] Step 2: 2-Butyl-benzofuran-3-carboxylic acid
[5-(4-tert-butyl-phenyl)-6-cyanomethoxy-naphthalen-2-ylmethyl]-amide.
A mixture of 2-butyl-benzofuran-3-carboxylic acid
[5-(4-tert-butyl-phenyl)-- 6-hydroxy-naphthalen-2-ylmethyl]-amide
(400 mg, 0.79 mmol), prepared in the previous step,
bromoacetonitrile (66 .mu.L, 0.95 mmol) and potassium carbonate
(547 mg, 3.96 mmol) in 20 mL of DMF was stirred under nitrogen at
room temperature for 19 h (overnight). The reaction was diluted
with ethyl acetate, extracted multiple times with water, dried
(MgSO.sub.4) and the solvent removed under reduced pressure to give
a light brown solid. Purification of the solid on a 40 g KP-SIL 60
.DELTA. Biotage column gave 2-butyl-benzofuran-3-carboxylic acid
[5-(4-tert-butyl-phenyl)-
-6-cyanomethoxy-naphthalen-2-ylmethyl]-amide (262 mg, 63%) as a
white solid, mp 162-164.degree. C.
[0272] Elemental Analysis for C.sub.36H.sub.36N.sub.2O.sub.3
Calc'd: C, 79.38; H, 6,66; N, 5.14 Found: C, 78.69; H, 6.72; N,
5.09
[0273] Step 3: 2-Butyl-benzofuran-3-carboxylic acid
[5-(4-tert-butyl-phenyl)-6-(1H-tetrazol-5-ylmethoxy)-naphthalen-2-ylmethy-
l]-amide. A mixture of 2-butyl-benzofuran-3-carboxylic acid
[5-(4-tert-butyl-phenyl)-6-cyanomethoxy-naphthalen-2-ylmethyl]-amide
(207 mg, 0.38 mmol), prepared in the previous step, sodium azide
(72.9 mg, 1.12 mmol) and ammonium chloride (58,7 mg, 1.10 mmol) in
10 mL of DMF was stirred under nitrogen at 100.degree. C. for 6 h.
If starting material remains additional quantities of sodium azide
and ammonium chloride are added until the reaction is complete by
TLC. The reaction was diluted with water, made basic by the
addition of 1 N NaOH and extracted multiple times with ethyl
acetate. The combined organic extracts were acidified by the
addition of 1 N HCl and then concentrated under reduced pressure.
The residue was diluted with water and the solid that formed was
collected by filtration and dried under reduced pressure to give
the title compound (186 mg, 84%) as a white solid, mp75-78.degree.
C.
[0274] Elemental Analysis for C.sub.36H.sub.37N.sub.5O.sub.3+0.31
H.sub.2O Calc'd: C, 72.88; H, 6.39; N, 11.80 Found: C, 71.52; H,
6.58; N, 11.83
EXAMPLE 28
(6-{[(2-Butyl-benzofuran-3-carbonyl)-amino]-methyl}-1-phenyl-naphthanen-2--
yloxy)-acetic acid
[0275] Step 1:
(6-{[(2-Butyl-benzofuran-3-carbonyl)-amino]-methyl}-1-pheny-
l-naphthanen-2-yloxy)-acetic acid. A mixture of
2-butyl-benzofuran-3-carbo- xylic acid
(6-hydroxy-5-phenyl-naphthalen-2-ylmethyl)-amide (63 mg, 0.14
mmol), prepared in step 1 of Example 24, methyl bromoacetate (16
.mu.L, 0.17 mmol) and potassium carbonate (100 mg, 0.70 mmol) in 3
mL of DMF was stirred under nitrogen at room temperature for 18 h
(overnight). The reaction was diluted with ethyl acetate, extracted
multiple times with water, one time with saturated NaCl, dried
(MgSO.sub.4) and the solvent removed under reduced pressure to give
81 mg of an off-white solid. Purification of the solid on 100 g of
silica gel (230-400 mesh) using 2:1 hexane:ethyl acetate as the
eluent gave 52 mg of a white solid. The solid was dissolved in 40
mL of methanol plus 6 mL of water. 1 N NaOH (100 .mu.L, 0.1 mmol)
was added and the mixture stirred under nitrogen at room
temperature for 18 h (overnight). The reaction was acidified by the
addition of 1 N HCl and then concentrated under reduced pressure to
remove the methanol. The solid present was collected by filtration
and dried under reduced pressure to give the title compound (30 mg,
62%) as a white solid, mp 180-183.degree. C.
[0276] Elemental Analysis for C.sub.32H.sub.29NO.sub.5 Calc'd: C,
75.72; H, 5.76; N, 2.76 Found: C, 75.23; H, 5.61; N, 2.68
EXAMPLE 29
2-[6-{[(2-Butyl-benzofuran-3-carbonyl)-amino]-methyl}-1-(4-chloro-phenyl)--
naphthalen-2-yloxy]-3-phenyl-propionic acid
[0277] Step 1:
2-[6-{[(2-Butyl-benzofuran-3-carbonyl)-amino]-methyl}-1-(4--
chloro-phenyl)-naphthalen-2-yloxy]-3-phenyl-propionic acid methyl
ester. A mixture of 2-butyl-benzofuran-3-carboxylic acid
[5-(4-chloro-phenyl)-6-hy- droxy-naphthalen-2-ylmethyl]-amide (248
mg, (0.511 mmol), prepared in step 1 of Example 26,
3-phenyl-2-trifluoromethanesulfonyloxy-propionic acid methyl ester
(299 mg, 0.96 mmol), prepared in step 2 of Example 7, and cesium
carbonate (304 mg, 0.93 mmol) in 30 mL of acetone was stirred under
nitrogen at room temperature for 20 h (overnight). The reaction was
concentrated under reduced pressure to remove the acetone. The
residue was partitioned between ethyl acetate and water. The
organic layer was separated and the aqueous layer extracted
multiple times with ethyl acetate. The combined organic extracts
were dried (MgSO.sub.4) and the solvent removed under reduced
pressure to give 436 mg of material. Purification of the material
on a 40 g KP-SIL 60 .DELTA. Biotage column using 6:1 hexane:ethyl
acetate as the eluent gave 2-[6-{[(2-butyl-benzofu-
ran-3-carbonyl)-amino]-methyl}-1-(4-chloro-phenyl)-naphthalen-2-yloxy]-3-p-
henyl-propionic acid methyl ester (263 mg, 80%) as a white solid
foam, mp 59-62.degree. C.
[0278] Elemental Analysis for C.sub.40H.sub.36ClNO.sub.5 Calc'd: C,
74.35; H, 5.62; N, 2.17 Found: C, 73.97; H, 5.62; N, 2.10
[0279] Step 2:
2-[6-{[(2-Butyl-benzofuran-3-carbonyl)-amino]-methyl}-1-(4--
chloro-phenyl)-naphthalen-2-yloxy]-3-phenyl-propionic acid. 1 N
NaOH (300 .mu.L, 0.30 mmol) was added under nitrogen to a solution
of
2-[6-{[(2-butyl-benzofuran-3-carbonyl)-amino]-methyl}-1-(4-chloro-phenyl)-
-naphthalen-2-yloxy]-3-phenyl-propionic acid methyl ester (182 mg,
0.28 mmol), prepared in the previous step, in 30 mL of methanol
plus 2.5 mL of water at room temperature. After the addition the
reaction was stirred at room temperature overnight. If starting
material remains additional 1 N NaOH is added until the reaction is
complete. A total of 900 .mu.L of 1 N NaOH was added. The reaction
was acidified by the addition of 1.6 mL of 1 N HCl and then
concentrated under reduced pressure. The solid that formed was
collected by filtration and dried under reduced pressure to give
the title compound (166 mg, 94%) as a white solid, mp
169-172.degree. C.
[0280] Elemental Analysis for C.sub.39H.sub.34ClNO.sub.5+0.28
H.sub.2O Calc'd: C, 73.51; H, 5.47; N, 2.20 Found: C, 72.82; H,
5.37; N, 2.14
EXAMPLE 30
Sodium;
2-[6-{[(2-Butyl-benzofuran-3-carbonyl)-amino]-methyl}-1-(4-methoxy-
-phenyl)-naphthalen-2-yloxy]-3-phenyl-propionate
[0281] Step 1:
2-[6-{[(2-Butyl-benzofuran-3-carbonyl)-amino]-methyl-1-(4-m-
ethoxy-phenyl)-naphthalen-2-yloxy]-3-phenyl-propionic acid methyl
ester. In the same manner as described in step 1 of Example 29,
2-[6-{[(2-butyl-benzofuran-3-carbonyl)-amino]-methyl}-1-(4-methoxy-phenyl-
)-naphthalen-2-yloxy]-3-phenyl-propionic acid methyl ester (109 mg,
69%) was obtained as a white solid, mp 103-105.degree. C.
[0282] Elemental Analysis for C.sub.41H.sub.39NO.sub.6 Calc'd: C,
76.73; H, 6.13; N, 2.18 Found: C, 76.66; H, 6.24; N, 2.16
[0283] Step 2: Sodium;
2-[6-{[(2-Butyl-benzofuran-3-carbonyl)-amino]-methy-
l}-1-(4-methoxy-phenyl)-naphthalen-2-yloxy]-3-phenyl-propionate. 1
N NaOH (200 .mu.L, 0.20 mmol) was added under nitrogen to
2-[6-{[(2-butyl-benzofuran-3-carbonyl)-amino]-methyl}-1-(4-methoxy-phenyl-
)-naphthalen-2-yloxy]-3-phenyl-propionic acid methyl ester (70.8
mg, 0.110 mmol), prepared in the previous step, in 10 mL of MeOH
plus 1 mL of water at room temperature. After a few hours at room
temperature a TLC showed that starting material remained. An
additional 200 .mu.L (0.20 mmol) of 1 N NaOH was added and the
reaction stirred at room temperature overnight. An additional 200
.mu.L (0.20 mmol) of 1 N NaOH was added and the reaction stirred at
room temperature for 2 h. 1 N HCl (650 .mu.L, 0.65 mmol) was added
and the reaction concentrated under reduced pressure to remove the
MeOH. The solid that formed was collected by filtration, rinsed
with water and dried under reduced pressure to give the title
compound (67 mg, 97%) was as an off-white solid, mp 138-142.degree.
C.
[0284] Elemental Analysis for C.sub.40H.sub.37NO.sub.6Na+1.05
H.sub.2O Calc'd: C, 71.85; H, 5.74; N, 2.09 Found: C, 71.97; H,
5.64; N, 2.05
EXAMPLE 31
2-Butyl-benzofuran-3-carboxylic acid
[5-bromo-6-(1H-tetrazol-5-ylmethoxy)--
naphthalen-2-ylmethyl]-methyl-amide
[0285] Step 1: (6-Methoxy-naphthalen-2-ylmethylene)-methyl-amine. A
mixture of an 8.03M solution of methylamine in ethanol (67 mL, 537
mmol) and 50 mL of methylene chloride was added dropwise under
nitrogen to a mixture of 6-methoxy-naphthalene-2-carbaldehyde (20
g, 107.4 mmol), magnesium sulfate (20 g) and 200 mL of methylene
chloride. The mixture stirred at room temperature under nitrogen
for 17 h. The MgSO.sub.4 was removed by filtration and the solvent
was removed under reduced pressure to give
(6-methoxy-naphthalen-2-ylmethylene)-methyl-amine (20.59 g, 96%) as
a yellow solid, mp 109-110.degree. C.
[0286] Elemental Analysis for C.sub.13H.sub.13NO Calc'd: C, 78.36;
H, 6.58; N, 7.03 Found: C, 77.10; H, 6.43; N, 7.19
[0287] Step 2: (6-Methoxy-naphthalen-2-ylmethyl)-methyl-amine.
(6-Methoxy-naphthalen-2-ylmethylene)-methyl-amine (20.0 g, 100
mmol), prepared in the previous step, was dissolved with heating in
300 mL of absolute ethanol. At room temperature, sodium borohydride
(3.783 g, 100 mmol) was added portion wise. The reaction stirred
under nitrogen for 18 h. 1N HCl was added to the reaction until pH
1 (litmus paper). The solvent was removed under reduced pressure
and the resulting residue was partitioned between methylene
chloride and water. The aqueous layer was made basic with 1N NaOH.
The aqueous layer was separated and extracted with methylene
chloride. The combined organic extracts were dried (MgSO.sub.4) and
solvent removed under reduced pressure to give
(6-methoxy-naphthalen-2-ylmethyl)-methyl-amine (18.80 g, 93.5%) as
an off-white solid, mp 96-104.degree. C.
[0288] Elemental Analysis for C.sub.13H.sub.15NO Calc'd: C, 77.58;
H, 7.51; N, 6.96 Found: C, 77.21; H, 7.38; N, 6.84
[0289] Step 3: (6-Hydroxy-naphthalene-2-ylmethyl)-methyl-ammonium;
bromide. (6-Methoxy-naphthalen-2-ylmethyl)-methyl-amine (1 8.48 g,
91.8mmol), prepared in the previous step, was suspended in 300 mL
of 48% HBr and under nitrogen the mixture was refluxed 18 h. The
solvent was removed under reduced pressure to give 28.8 g of a
reddish brown solid. The solid was taken up in isopropanol and
stirred for 1 h. A solid was collected by filtration and dried
under reduced pressure to give
(6-hydroxy-naphthalene-2-ylmethyl)-methyl-ammonium; bromide (5.5 g,
22%) as a reddish brown solid, mp182-184.degree. C.
[0290] Elemental Analysis for C.sub.12H.sub.14BrNO Calc'd: C,
53.75; H, 5.26; N, 5.22 Found: C, 50.77; H, 5.61; N, 4.89
[0291] Step 4: 2-Butyl-benzofuran-3-carboxylic acid
(6-hydroxy-naphthalen-2-ylmethyl)-methyl-amide.
2-Butyl-benzofuran-3-carb- onyl chloride, prepared in step 2 of
Example 3, in 40 mL of methylene chloride was added under nitrogen
dropwise over 1 h to a solution of
(6-hydroxy-naphthalen-2-ylmethyl)-methyl-ammonium; bromide (2.81 g,
10.5 mmol), prepared in the previous step, in 100 mL of anhydrous
pyridine at ice bath temperature. After the addition the ice bath
was removed and the reaction stirred at room temperature for 18 h
(overnight). The reaction was acidified with 1N HCl and extracted
three times with methylene chloride. The organic extracts were
combined, dried (MgSO.sub.4) and the solvent removed under reduced
pressure to give 3.19 g of a brown oil. The oil was chromatographed
on 600 g of silica gel (230-400 mesh) using 5% methanol saturated
with ammonia in methylene chloride as the eluent in order to remove
any acid impurities. The material isolated was chromatographed on
300 g silica gel (230-400 mesh) using 5%-15% ethyl acetate in
methylene chloride as the eluent. Isolation of the desired
component gave 2-butyl-benzofuran-3-carboxylic acid
(6-hydroxy-naphthalen-2-ylmethyl)-methyl-amide (0.588 g, 14%) as a
yellow solid, mp 110-113.degree. C.
[0292] Elemental Analysis for C.sub.25H.sub.25NO.sub.3 Calc'd: C,
77.49; H, 6.50; N, 3.61 Found: C, 76.58; H, 6.54; N, 3.43
[0293] Step 5: 2-Butyl-benzofuran-3-carboxylic acid
(5-bromo-6-hydroxy-naphthalen-2-ylmethyl)-methyl-amide. A solution
of bromine in 40 mL glacial acetic acid was added dropwise under
nitrogen over 2.5 h to a solution of
2-butyl-benzofuran-3-carboxylic acid
(6-hydroxy-naphthalen-2-ylmethyl)-methyl-amide (0.5364 g, 1.358
mmol), prepared in the previous step, in 60 mL of glacial acetic
acid. The reaction stirred for 20 h (overnight). The solvent was
removed under reduced pressure. The residue was diluted with
methylene chloride, extracted with 5% NaHCO.sub.3, dried
(MgSO.sub.4) and the solvent removed under reduced pressure to give
2-butyl-benzofuran-3-carboxylic acid
(5-bromo-6-hydroxy-naphthalen-2-ylmethyl)-methyl-amide (0.6981 g,
100%.) as a light yellow foam, MS m/z: 466 [M+H].sup.+.
[0294] Elemental Analysis for C.sub.25H.sub.24BrNO.sub.3 Calc'd: C,
64.38; H, 5.19; N, 3.00 Found: C, 63.54; H, 4.88; N, 2.93
[0295] Step 6: 2-Butyl-benzofuran-3-carboxylic acid
(5-bromo-6-cyanomethoxy-naphthalen-2-ylmethyl)-methyl-amide. A
mixture of 2-butyl-benzofuran-3-carboxylic acid
(5-bromo-6-hydroxy-naphthalen-2-ylme- thyl)-methyl-amide (0.5587 g,
1.2 mmol), prepared in the previous step, bromoacetonitrile (0.10
mL, 1.44 mmol) and potassium carbonate (0.83 g, 6 mmol) in 10 mL of
DMF was stirred under nitrogen at room temperature for 18 h
(overnight). The reaction was diluted with ethyl acetate and
extracted multiple times with water. The organic layer was dried
(MgSO.sub.4) and the solvent removed under reduced pressure to give
a brown oil. The oil was chromatographed on a 90 g KP-SIL 60
.DELTA. Biotage column using 5% ethyl acetate in methylene chloride
as the eluent. Isolation of the desired product gave
2-butyl-benzofuran-3-carbox- ylic acid
(5-bromo-6-cyanomethoxy-naphthalen-2-ylmethyl)-methyl-amide (0.48
g, 79%) as a clear oil, MS m/z: 505 [M+H].sup.+.
[0296] Elemental Analysis for C.sub.27H.sub.25BrN.sub.2O.sub.3
Calc'd: C, 64.16; H, 4.99; N, 5.54 Found: C, 64.08; H, 5.08; N,
5.34
[0297] Step 7: 2-Butyl-benzofuran-3-carboxylic acid [5-bromo-6-(1
Htetrazol-5-ylmethoxy)-naphthalen-2-ylmethyl]-methyl-amide. A
mixture of 2-butyl-benzofuran-3-carboxylic acid
(5-bromo-6-cyanomethoxy-naphthalen-2- -ylmethyl)-methyl-amide (0.3
g, 0.59 mmol), prepared in the previous step, sodium azide (0.116
g, 1.78 mmol) and ammonium chloride (0.095 g, 1.78 mmol) in 12 mL
DMF was stirred under nitrogen at 100.degree. C. for 6.5 h. The
reaction was diluted with water, made basic with 1N NaOH, and
extracted three times with ethyl acetate. The organic layers were
combined, acidified with 1N HCl, dried (MgSO.sub.4) and the solvent
removed under reduced pressure to give an oily residue. The oil was
diluted with water and the solid that formed was collected by
filtration, rinsed with water and dried under reduced pressure to
give the title compound (0.20 g, 63%) as an off white solid, mp
190-194.degree. C.
[0298] Elemental Analysis for C.sub.27H.sub.28BrN.sub.5O.sub.3+0.12
H.sub.2O Calc'd: C, 58.90; H, 4.80; N, 12.72 Found: C, 57.80; H,
4.72; N, 12.34
EXAMPLE 32
2-Ethyl-benzofuran-3-carboxylic acid
[5-bromo-6-(1H-tetrazol-5-ylmethoxy)--
naphthalen-2-ylmethyl]-methyl-amide
[0299] Step 1: 6-Methylaminomethyl-naphthalene-2-ol.
(6-Hydroxy-naphthalene-2-ylmethyl)-methyl-ammonium; bromide (9 g,
33.56 mmol), prepared in step 3 of Example 31, was taken up in 300
mL of water and made basic by the addition of with 5% sodium
bicarbonate. Some solid remained in the solution, which was removed
by filtration. The filtrate was extracted with ethyl acetate
multiple times. The organic extracts were combined, dried
(MgSO.sub.4) and the solvent removed under reduced pressure to give
6-methylaminomethyl-naphthalene-2-ol (5 g, 80%) as a tan solid,
mp168-169.degree. C.
[0300] Elemental Analysis for C.sub.12H.sub.13NO Calc'd: C, 76.98;
H, 7.00; N, 7.48 Found: C, 75.70; H, 6.99; N, 7.16
[0301] Step 2: 2-Ethyl-benzofuran-3-carboxylic acid
(6-hydroxy-naphthalen-2-ylmethyl)-methyl-amide.
2-Ethyl-benzofuran-3-carb- onyl chloride, prepared in step 2 of
Example 21, in 50 mL of anhydrous THF was added under nitrogen
dropwise over 1 h to a suspension of
6-methylaminomethyl-naphthalen-2-ol (1.48 g, 7.9 mmol), prepared in
the previous step, and triethylamine (1.1 mL, 7.9 mmol) in 150 mL
anhydrous THF at room temperature. The reaction stirred at room
temperature for 20 h (overnight). The solid present was removed by
filtration and the filtrate concentrated under reduced pressure to
give a brown foam. The foam was dissolved in ethyl acetate and
extracted with 1 N HCl. The organic layer was dried (MgSO.sub.4)
and the solvent removed under reduced pressure to give a brown oil
which solidified when treated with hexane. The crystals were
triturated with hexane and dried under reduced pressure to give
2-ethyl-benzofuran-3-carboxylic acid
(6-hydroxy-naphthalen-2-ylmethyl)-methyl-amide (2.38 g, 84%) as tan
solid, mp 80-90.degree. C.
[0302] Elemental Analysis for C.sub.23H.sub.21NO.sub.3 Calc'd: C,
76.86; H, 5.89; N, 3.90 Found: C, 74.31; H, 5.90; N, 3.48
[0303] Step 3: 2-Ethyl-benzofuran-3-carboxylic acid
(5-bromo-6-hydroxy-naphthalen-2-ylmethyl)-methyl-amide. A solution
of bromine in 50 mL glacial acetic acid was added dropwise under
nitrogen over 3 h to a solution of 2-ethyl-benzofuran-3-carboxylic
acid (6-hydroxy-naphthalen-2-ylmethyl)-methyl-amide (1.5 g, 4.17
mmol), prepared in the previous step, in 150 mL glacial acetic acid
at room temperature. The reaction stirred for 17 h (overnight). The
solvent was removed under reduced pressure. The residue was
dissolved in methylene chloride, extracted with 5% sodium
bicarbonate, dried (MgSO.sub.4) and solvent removed under reduced
pressure to give 2-ethyl-benzofuran-3-carbo- xylic acid
(5-bromo-6-hydroxy-naphthalen-2-ylmethyl)-methyl-amide (1.74 g,
95%) as a brown solid, mp 176-178.degree. C.
[0304] Elemental Analysis for C.sub.23H.sub.20BrNO.sub.3 Calc'd: C,
63.03; H, 4.60; N, 3.20 Found: C, 62.70; H, 4.75; N, 2.87
[0305] Step 4: 2-Ethyl-benzofuran-3-carboxylic acid
(5-bromo-6-cyanomethoxy-naphthalen-2-ylmethyl)-methyl-amide. A
mixture of 2-ethyl-benzofuran-3-carboxylic acid
(5-bromo-6-hydroxy-naphthalen-2-ylme- thyl)-methyl-amide (0.5 g,
1.14 mmol), prepared in the previous step, bromoacetonitrile (95
.mu.L, 1.36 mmol) and potassium carbonate (0.79 g, 5.7 mmol) in 20
mL of DMF was stirred under nitrogen at room temperature for 18 h
(overnight). The reaction was diluted with ethyl acetate and
extracted multiple times with water. The organic layer was dried
(MgSO.sub.4) and the solvent removed under reduced pressure to give
a dark brown oil. The oil was chromatographed on 50 g of silica gel
(230-400 mesh) using 5% ethyl acetate in methylene chloride as the
eluent. Isolation of the desire component gave
2-ethyl-benzofuran-3-carbo- xylic acid
(5-bromo-6-cyanomethoxy-naphthalen-2-ylmethyl)-methyl-amide (0.39
g, 72%) as a light yellow foam, MS m/z: 477 [M+H].sup.+.
[0306] Elemental Analysis for C.sub.25H.sub.21BrN.sub.2O.sub.3
Calc'd: C, 62.90; H, 4.43; N, 5.87 Found: C, 62.92; H, 4.44; N,
5.80
[0307] Step 5: 2-Ethyl-benzofuran-3-carboxylic acid
[5-bromo-6-(1H-tetrazol-5-ylmethoxy)-naphthalen-2-ylmethyl]-methyl-amide.
A mixture of 2-ethyl-benzofuran-3-carboxylic acid
(5-bromo-6-cyanomethoxy- -naphthalen-2-ylmethyl)-methyl-amide (0.25
g, 0.5237 mmol), prepared in the previous step, sodium azide (0.10
g, 1.57 mmol) and ammonium chloride (0.084 g, 1.57 mmol) in 12 mL
DMF was stirred under nitrogen at 100.degree. C. for 5 h. The
reaction was diluted with water, made basic with 1N NaOH and
extracted four times with ethyl acetate. The combined organic
extracts were acidified with 1N HCl, the solvent removed under
reduced pressure and the resulting residue diluted with water. The
solid foam that formed was collected by filtration and dried under
reduced pressure to give the title compound (0.15 g, 56%) as a tan
foam, MS m/z: 520 [M+H].sup.+.
[0308] Elemental Analysis for C.sub.25H.sub.22BrN.sub.5O.sub.3+1.5
H.sub.2O Calc'd: C, 57.40; H, 4.30; N, 13.39 Found: C, 56.45; H,
4.51; N, 13.36
EXAMPLE 33
1-Phenyl-5-propyl-1H-pyrazole-4-carboxylic acid [5-bromo-6-(1H-
tetrazol-5-ylmethoxy)-naphthalen-2-ylmethyl]-methyl-amide
[0309] Step 1: 1-Phenyl-5-propyl-1H-pyrazole-4-carboxylic acid
(6-hydroxy-naphthalen-2ylmethyl)-methyl-amide. 1-Phenyl-5-propyl-1
H-pyrazole-4-carbonyl chloride (14.82 g, 59.6 mmol) in 60 mL of
methylene chloride was added under nitrogen dropwise over 10
minutes to a solution of
(6-hydroxy-naphthalene-2-ylmethyl)-methyl-ammonium; bromide,
prepared in step 3 of Example 31, in 150 mL of anhydrous pyridine.
The reaction stirred at room temp for 17 h (overnight). The
reaction was diluted with methylene chloride and extracted with 1 N
HCl. The organic layer was separated and the aqueous layer
extracted two times with methylene chloride. The organic extracts
were combined, dried (MgSO.sub.4) and solvent removed under reduced
pressure to give a brown oil. This oil was dissolved in 350 mL of
methanol, 100 mL water and 130 mL 1N NaOH and refluxed for 20 h
(overnight). The solvent was removed under reduced pressure and the
residue dissolved in methylene chloride. Ice was added to the
mixture and then 130 mL of 1N HCl was added slowly. The organic
layer was separated and the aqueous layer was extracted three more
times with methylene chloride. The organic extracts were combined,
dried (MgSO.sub.4) and solvent removed under reduced pressure to
give a brown oil (20.23 g). The oil was chromatographed on 1 Kg of
silica gel (230-400 mesh) using methanol saturated with ammonia gas
and methylene chloride as the eluent. Isolation of the desired
component gave 1-Phenyl-5-propyl-1H-pyrazole-4-carboxylic acid
(6-hydroxy-naphthalen-2yl- methyl)-methyl-amide (10.6 g, 89%) as a
brown solid. Crystallization of the material from methanol and
methylene chloride gave yellow crystals, mp 138-141.degree. C.
[0310] Elemental Analysis for C.sub.25H.sub.25N.sub.3O.sub.2
Calc'd: C, 75.16; H, 6.31; N, 10.52 Found: C, 74.74; H, 6.18; N,
10.41
[0311] Step 2: 1-Phenyl-5-propyl-1H-pyrazole-4-carboxylic acid
(5-bromo-6-hydroxy-naphthalen-2-ylmethyl)-methyl-amide.
1-Phenyl-5-propyl-1H-pyrazole-4-carboxylic acid
(6-hydroxy-naphthalen-2yl- methyl)-methyl-amide (3.2 g, 8 mmol),
prepared in the previous step, was dissolved in 300 mL glacial
acetic acid (with warming). A solution of bromine (0.41 mL, 8 mmol)
in 50 mL of glacial acetic acid was added under nitrogen dropwise
over 2 h to the reaction at room temperature. After the addition
the reaction stirred for 2 days. The solvent was removed under
reduced pressure and the residue diluted with methylene chloride.
The organic layer was extracted two times with 5% NaHCO.sub.3,
dried (MgSO.sub.4) and the solvent removed under reduced pressure
to give 1-phenyl-5-propyl-1H-pyrazole-4-carboxylic acid
(5-bromo-6-hydroxy-naphth- alen-2-ylmethyl)-methyl-amide (3.77 g,
98.5%) as a pink solid, mp 205-207.degree. C.
[0312] Elemental Analysis for C.sub.25H.sub.24BrN.sub.3O.sub.2
Calc'd: C, 62.77; H, 5.06; N, 8.78 Found: C, 62.28; H, 4.88; N,
8.65
[0313] Step 3: 1-Phenyl-5-propyl-1H-pyrazole-4-carboxylic acid
(5-bromo-6-cyanomethoxy-naphthalen-2-ylmethyl)-methyl-amide. A
mixture of 1-phenyl-5-propyl-1H-pyrazole-4-carboxylic acid
(5-bromo-6-hydroxy-naphth- alen-2-ylmethyl)-methyl-amide (0.5 g,
1.045 mmol), prepared in the previous step, bromoacetonitrile
(0.087 mL, 1.25 mmol) and potassium carbonate (0.72 g, 5.23 mmol)
in 10 mL of DMF was stirred under nitrogen at room temperature for
2 days (over the weekend). The reaction was diluted with ethyl
acetate and extracted multiple times with water. The organic layer
was dried (MgSO.sub.4) and the solvent removed under reduced
pressure to give a brown oil (0.364 g). Purification of the oil on
a 90 g KP-SIL 60 .DELTA. Biotage column using 15% ethyl acetate in
methylene chloride as the eluent gave
1-phenyl-5-propyl-1H-pyrazole-4-car- boxylic acid
(5-bromo-6-cyanomethoxy-naphthalen-2-ylmethyl)-methyl-amide (0.32
g, 59%) as an off white solid, mp 76-80.degree. C.
[0314] Elemental Analysis for C.sub.27H.sub.25BrN.sub.4O.sub.2
Calc'd: C, 62.68; H, 4.87; N, 10.83 Found: C, 62.44; H, 4.83; N,
10.69
[0315] Step 4: 1-Phenyl-5-propyl-1H-pyrazole-4-carboxylic acid
[5-bromo-6-(1H-tetrazol-5-ylmethoxy)-naphthalen-2-ylmethyl]-methyl-amide.
A mixture of 1-phenyl-5-propyl-1H-pyrazole-4-carboxylic acid
(5-bromo-6-cyanomethoxy-naphthalen-2-ylmethyl)-methyl-amide (0.30
g, 0.58 mmol), prepared in the previous step, sodium azide (0.113
g, 1.74 mmol) and ammonium chloride (0.093 g, 1.74 mmol) in 10 mL
of DMF was stirred under nitrogen at 100.degree. C. for 6 h. By TLC
the reaction was not complete. Sodium azide (0.113 g, 1.74 mmol)
and ammonium chloride (0.093 g, 1.74 mmol) were added and the
reaction was stirred under nitrogen at 100.degree. C. for 6.5 h.
The reaction was diluted with water, made basic by the addition of
1N NaOH and extracted five times with ethyl acetate. The combined
organic extracts were acidified with 1N HCl and the solvent removed
under reduced pressure. The residue was diluted with water and the
solid that formed was collected by filtration and dried under
reduced pressure to give the title compound (0.108 g, 33%) as a tan
solid, mp 75-85.degree. C.
[0316] Elemental Analysis for C.sub.27H.sub.2rBrN.sub.7O.sub.2+0.5
EtOAc Calc'd: C, 57.62; H, 5.00; N, 16.22 Found: C, 57.21; H, 4.97;
N, 16.22
EXAMPLE 34
1-Benzyl-1H-indole-3-carboxylic acid
[5-bromo-6-(1H-tetrazol-5-ylmethoxy)--
naphthalen-2-ylmethyl]-methyl-amide
[0317] Step 1:1-Benzyl-1H-indole-3-carbonyl chloride. A mixture of
1-benzyl-1H-indole-3-carboxylic acid (3.36 g, 13.37 mmol), oxalyl
chloride (5.83 mL, 66.85 mmol), 100 mL methylene chloride and a
catalytic amount of DMF was stirred at room temperature under
nitrogen for 18 h (overnight). The solvent was removed under
reduced pressure. To remove excess oxalyl chloride benzene was
added and the solvent removed under reduced pressure to give
1-benzyl-1H-indole-3-carbonyl chloride as a brown oil (13.37 mmol)
which was immediately used in step 2 without additional
purification.
[0318] Step 2: 1-Benzyl-1H-indole-3-carboxylic acid
(6-hydroxy-naphthalen-2-ylmethyl)-methyl-amide.
1-Benzyl-1H-indole-3-carb- onyl chloride, prepared in the previous
step, in 50 mL of anhydrous THF was added dropwise under nitrogen
over 2 h to a mixture of 6-methylaminomethyl-naphthalen-2-ol (2.5
g, 13.37 mmol), prepared in step 1 of Example 32, and triethylamine
(1.86 mL, 13.37 mmol) in 300 mL of anhydrous THF at room
temperature. The reaction stirred for 17.5 h (overnight). A trace
amount of solid was removed by filtration and the filtrate was
concentrated under reduced pressure to give a brown oil. The oil
was diluted with ethyl acetate, extracted two times with 1N HCl,
dried (MgSO.sub.4) and the solvent removed under reduced pressure
to give 1-benzyl-1H-indole-3-carboxylic acid
(6-hydroxy-naphthalen-2-ylmethyl)-me- thyl-amide (5.83 g, 100%) as
a brown foam, MS m/z: 421 [M+H].sup.+.
[0319] Elemental Analysis for C.sub.28H.sub.24N.sub.2O.sub.2
Calc'd: C, 79.98; H, 5.75; N, 6.66 Found: C, 78.46; H, 5.95; H,
6.31
[0320] Step 3: 1-Benzyl-1H-indole-3-carboxylic acid
(5-bromo-6-hydroxy-naphthalen-2-ylmethyl)-methyl-amide. A solution
of bromine (0.37 mL, 0.7134 mmol) in 60 mL glacial acetic acid was
added dropwise under nitrogen over 2 h to a solution of
1-benzyl-1H-indole-3-ca- rboxylic acid
(6-hydroxy-naphthalen-2-ylmethyl)-methyl-amide (3.0 g, 0.713 mmol),
prepared in the previous step, in 300 mL glacial acetic acid at
room temperature. The reaction stirred for 18 h (overnight). The
solvent was removed under reduced pressure. The resulting residue
was diluted with ethyl acetate and extracted with 5% sodium
bicarbonate. A solid precipitated from the organic layer and was
collected by filtration. The filtrate was dried (MgSO.sub.4) and
concentrated under reduced pressure to give a tan solid. The two
solids were combined and taken up in a mixture of ethyl acetate and
isopropanol. A certain amount of material (1.0 g) would not
dissolve upon heating and was removed by filtration. The filtrate
was allowed to cool and upon cooling crystals formed. The crystals
were collected by filtration and dried under reduced pressure to
give 1-benzyl-1H-indole-3-carboxylic acid
(5-bromo-6-hydroxy-naphthalen-2- -ylmethyl)-methyl-amide (0.766 g,
22%) as a tan solid, mp 181-182.degree. C.
[0321] Elemental Analysis for C.sub.28H.sub.23BrN.sub.2O.sub.2
Calc'd: C, 67.34; H, 4.64; N, 5.61 Found: C, 66.59; H, 4.88; N,
5.34
[0322] Step 4: 1-Benzyl-1H-indole-3-carboxylic acid
(5-bromo-6-cyanomethoxy-naphthalen-2-ylmethyl)-methyl-amide. A
mixture of 1-benzyl-1H-indole-3-carboxylic acid
(5-bromo-6-hydroxy-naphthalen-2-ylme- thyl)-methyl-amide (1.589 g,
3.18 mmol), prepared in the previous step, bromoacetonitrile (0.265
mL, 3.8 mmol) and potassium carbonate (2.2 g, 15.9 mmol) in 15 mL
DMF was stirred under nitrogen at room temperature for 20 h
(overnight). The reaction was diluted with ethyl acetate and
extracted five times with water. The organic layer was dried
(MgSO.sub.4) and the solvent removed under reduced pressure to give
1.78 g of a brown foam. The foam was chromatographed on 500 g
silica gel (230-400 mesh) using ethyl acetate in methylene chloride
as the eluent. Isolation of the desired product gave
1-benzyl-1H-indole-3-carboxylic acid
(5-bromo-6-cyanomethoxy-naphthalen-2-ylmethyl)-methyl-amide (0.834
mg, 47%) as a white foam, MS m/z: 538 [M+H].sup.+.
[0323] Elemental Analysis for C.sub.30H.sub.24BrN.sub.3O.sub.2
Calc'd: C, 66.92; H, 4.49; N, 7.80 Found: C, 66.31; H, 4.27; N,
7.43
[0324] Step 5: 1-Benzyl-1H-indole-3-carboxylic acid
[5-bromo-6-(1H-tetrazol-5-ylmethoxy)-naphthalen-2-ylmethyl]-methyl-amide.
A mixture of 1-benzyl-1H-indole-3-carboxylic acid
(5-bromo-6-cyanomethoxy- -naphthalen-2-ylmethyl)-methyl-amide
(0.7725 g, 1.44 mmol), prepared in the previous step, sodium azide
(0.28 g, 4.3 mmol) and ammonium chloride (0.23 g, 4.3 mmol) in 15mL
DMF was stirred under nitrogen for 4 h at 100.degree. C.. The
reaction was diluted with water, made basic with 1N NaOH, and
extracted five times with ethyl acetate. The ethyl acetate layer
was acidified with 1N HCl and the solvent was removed under reduced
pressure to give 0.133 g of the desired compound as an off-white
solid. The aqueous layer was acidified with 1N HCl. The solution
sat at room temperature for 18 h (overnight). A solid had
precipitated from solution and was collected by filtration, rinsed
with water, and dried under reduced pressure to give the title
compound (0.4962 g, 60%) as an off white solid, mp 197-198.degree.
C.
[0325] Elemental Analysis for C.sub.30H.sub.25BrN.sub.6O.sub.2
Calc'd: C, 61.97; H, 4.33; N, 14.45 Found: C, 61.26; H, 4.18; N,
13.96
EXAMPLE 35
2-Butyl-benzofuran-3-carboxylic acid
methyl-[6-(1H-tetrazol-5-ylmethoxy)-n-
aphthalen-2ylmethyl]-methyl-amide.
[0326] Step 1: 2-Butyl-benzofuran-3-carboxylic acid
(6-cyanomethoxy-naphthalen-2ylmethyl)-methyl-amide. A mixture of
2-butyl-benzofuran-3-carboxylic acid
(6-hydroxy-naphthalen-2-ylmethyl)-me- thyl-amide (0.90 g, 2.32
mmol), prepared in step-4 of Example 31, bromoacetonitrile (0.194
mL, 2.79 mmol) and potassium carbonate (1.6 g, 11.6 mmol) in 10 mL
DMF was stirred under nitrogen at room temperature for 24 h
(overnight). The reaction was diluted with ethyl acetate and
extracted five times with water. The organic layer was dried
(MgSO.sub.4) and the solvent removed under reduced pressure to give
2-butyl-benzofuran-3-carboxylic acid
(6-cyanomethoxy-naphthalen-2ylmethyl- )-methyl-amide (0.94 g, 95%)
as a brown oil, MS m/z: 427 [M+H].sup.+.
[0327] Elemental Analysis for C.sub.27H.sub.26N.sub.2O.sub.3
Calc'd: C, 76.03; H, 6.14; N, 6.57 Found: C, 75.71; H, 5.93; N,
6.50
[0328] Step 2: 2-Butyl-benzofuran-3-carboxylic acid
methyl-[6-(1H-tetrazol-5-ylmethoxy)-naphthalen-2ylmethyl]-methyl-amide.
A mixture of 2-butyl-benzofuran-3-carboxylic acid
(6-cyanomethoxy-naphthale- n-2ylmethyl)-methyl-amide (0.8 g, 1.875
mmol), prepared in the previous step, sodium azide (0.365 g, 5.6
mmol) and ammonium chloride (0.30 g, 5.6 mmol) in 15 mL of DMF was
stirred under nitrogen at 100.degree. C. for 4.5 h. The reaction
was diluted with water, made basic by the addition of 1 N NaOH and
extracted five times with ethyl acetate. The organic layer was
acidified with 1N HCl and the solvent removed under reduced
pressure to give a brown oil. The aqueous layer was acidified with
1N HCl and concentrated under reduced pressure until a brown oil
precipitated. The two oils were combined to give 0.79 g of a brown
oil. This oil was dissolved in 1N NaOH and acidified with 1N HCl
until a solid precipitated. This solid was collected by filtration
and dried under reduced pressure to give the title compound (0.7652
g, 87%) as an off white solid, mp 78-84.degree. C., MS m/z: 470
[M+H].sup.+.
[0329] Elemental Analysis for C.sub.27H.sub.27N.sub.5O.sub.3+0.1
H.sub.2O Calc'd: C, 68.80; H, 5.82; N, 14.86 Found: C, 67.90; H,
5.57; N, 14.50
EXAMPLE 36
2-Butyl-1-methyl-1H-indole-3-carboxylic acid
[5-bromo-6-(1H-tetrazol-5-ylm-
ethoxy)-naphthalen-2-ylmethyl]-methyl-amide.
[0330] Step 1: 2-Butyl-l-methyl-1H-indole. Sodium hydride (60% oil
disperson; 1.52 g, 38.0 mmol) was added under nitrogen in portions
over 5 minutes to a solution of 2-butyl-1H-indole (5.00 g, 28.9
mmol) in 150 mL of anhydrous DMF at room temperature. After the
addition the reaction was stirred at room temperature for 1.25 h.
Methyl iodide (3.60 mL, 57.8 mmol) was then added and the reaction
stirred at room temperature for 3.5 h. 1 N HCl was added to the
reaction until the evolution of gas ceased. The reaction was
diluted with ethyl acetate, extracted multiple times with water,
dried (MgSO.sub.4) and the solvent removed under reduced pressure
to give 2-butyl-1-methyl-1H-indole (5.70 g, 100%) as a yellow oil,
MS m/z: 188 [M+H].sup.+.
[0331] Elemental Analysis for C.sub.13H.sub.17N Cala'd: C, 83.37;
H, 9.15; N, 7.48 Found: C, 83.41; H, 9.58; N, 6.82
[0332] Step 2:
1-(2-Butyl-1-methyl-1H-indol-3-yl)-2,2,2-trichloro-ethanone- .
Trichloroacetyl chloride (7.26 mL, 65.0 mmol) in 20 mL of methylene
chloride was added under nitrogen dropwise over 30 minutes to a
solution of 2-butyl-1-methyl-1 H-indole (4.87 g, 26.0 mmol),
prepared in the previous step, and triethylamine (9.06 mL, 65.0
mmol) in 100 mL of methylene chloride at ice-bath temperature.
After the addition the reaction was stirred at ice-bath temperature
for 5 h. The ice-bath was removed and the stirring continued at
room temperature for 16 h (overnight). By TLC starting material
remained. Triethylamine (3.62 mL, 26.0 mmol) was added followed by
the dropwise addition over 15 minutes of trichloroacetyl chloride
(2.90 mL, 2.60 mmol) in 10 mL of methylene chloride. After the
addition the reaction was stirred at room temperature 3 h. The
reaction was extracted with 1 N HCl, 5% NaHCO.sub.3, dried
(MgSO.sub.4) and the solvent removed under reduced pressure to give
16.46 g of a dark brown mushy solid. Purification of the solid on 1
Kg of silica gel (230-400 mesh) using 6:1 hexane: methylene
chloride to 4:1 hexane:methylene chloride as the eluents gave
1-(2-butyl-1-methyl-1H-indo- l-3-yl)-2,2,2-trichloro-ethanone (5.54
g, 64%) as a brown solid, mp 112-115.degree. C.
[0333] Elemental Analysis for C.sub.15H.sub.16C.sub.13NO Calc'd: C,
54.16; H, 4.85; N, 4.21 Found: C, 54.50; H, 4.88; N, 4.14
[0334] Step 3: 2-Butyl-1-methyl-1H-indole-3-carboxylic acid. A
mixture of
1-(2-butyl-1-methyl-1H-indol-3-yl)-2,2,2-trichloro-ethanone (4.87
g, 14.7 mmol), prepared in the previous step, and 1 N NaOH (73.5
mL, 73.5 mmol) in 350 mL of THF was refluxed under nitrogen for
2.25 h. After cooling to room temperature 1 N HCl (80 mL, 80 mmol)
was added and then the solvent was removed under reduced pressure.
The residue was partitioned between 1 N HCl and methylene chloride.
The organic layer was separated and the aqueous layer extracted
three times with methylene chloride. The combined extracts were
dried (MgSO.sub.4) and the solvent removed under reduced pressure
to give 2-butyl-1-methyl-1H-indole-3-carboxylic acid (3.44 g, 100%)
as a brown solid, mp 163-165.degree. C.
[0335] Elemental Analysis for C.sub.14H.sub.17NO.sub.2 Calc'd: C,
72.70; H, 7.41; N, 6.06 Found: C, 72.20; H, 7.45; N, 5.93
[0336] Step 4: 2-Butyl-1-methyl-1H-indole-3-carbonyl chloride.
Oxalyl chloride (5.89 mL, 66.1 mmol) was added under nitrogen to a
solution of 2-butyl-1-methyl-1H-indole-3-carboxylic acid (3.06 g,
13.2 mmol), prepared in the previous step, in 100 mL of methylene
chloride at room temperature. There was an immediate evolution of
gas. After the addition the reaction was stirred at room
temperature for 2 h. The solvent was removed under reduced
pressure. To remove excess oxalyl chloride the residue was
dissolved in benzene and the solvent removed under reduced pressure
to give 2-butyl-1-methyl-1H-indole-3-carbonyl chloride as a brown
oil. The material was immediately used without additional
purification.
[0337] Step 5: 5-Bromo-6-methoxy-naphthalene-2-carbaldehyde.
Bromine (556 .mu.L, 10.8 mL) in 10 mL of glacial HOAc was added
under nitrogen dropwise over 1 h to a solution of
6-methoxy-naphthalene-2-carbaldehyde (2.01 g, 10.8 mmol) in 25 mL
of glacial HOAc at room temperature. After the addition the
reaction was stirred at room temperature for 2 h. The solid was
collected by filtration, rinsed with glacial HOAc and dried under
reduced pressure to give
5-bromo-6-methoxy-naphthalene-2-carbaldehy- de (2.27 g, 79%) as a
tan solid, mp 148-150.degree. C.
[0338] Elemental Analysis for C.sub.12H.sub.9BrO.sub.2 Calc'd: C,
54.37; H, 3.42; N, 0.00 Found: C, 54.26; H, 3.28; N, 0.00
[0339] Step 6:
(5-Bromo-6-methoxy-naphthalen-2-ylmethylene)-methyl-amine.
Methylamine (2.35 mL of an 8.03 M solution in ethanol, 18.8 mmol)
in 5 mL of methylene chloride was added under nitrogen dropwise
over 5 minutes to a mixture of
5-bromo-6-methoxy-naphthalene-2-carbaldehyde (1.00 g, 3.77 mmol),
prepared in the previous step, and 3 g of anhydrous MgSO.sub.4 in
20 mL of methylene chloride at room temperature. After the addition
the reaction was stirred at room temperature for 21 h (overnight).
The reaction was filtered and the filtrate concentrated under
reduced pressure to give
(5-bromo-6-methoxy-naphthalen-2-ylmethylene)-methyl-amin- e (1.05
g, 100%) as a light tan solid, mp 105-107.degree. C.
[0340] Elemental Analysis for C.sub.13H.sub.12BrNO Calc'd: C,
56.14; H, 4.35; N, 5.04 Found: C, 56.12; H, 4.37; N, 4.97
[0341] Step 7:
(5-Bromo-6-methoxy-naphthalen-2-ylmethyl)-methyl-amine. Sodium
borohydride (131 mg, 3.47 mmol) was added under nitrogen to a warm
solution of
(5-bromo-6-methoxy-naphthalen-2-ylmethylene)-methyl-amine (950 mg,
4.41 mmol), prepared in the previous step, in 30 mL of absolute
ethanol. After the addition the reaction was stirred at room
temperature for 19 h (overnight). 1 N HCl was added dropwise until
the reaction was pH.about.1 (litmus paper). The solvent was removed
under reduced pressure and the residue partitioned between
methylene chloride and water. The aqueous layer was made basic by
the addition of 1 N NaOH. The organic layer was separated and the
aqueous layer was extracted three times with methylene chloride.
The combined extracts were dried (MgSO.sub.4) and the solvent
removed under reduced pressure to give (5-bromo-6-methoxy-naphtha-
len-2-ylmethyl)-methyl-amine (900 mg, 94%) as an off-white solid,
mp 41-45.degree. C.
[0342] Elemental Analysis for C.sub.13H.sub.14BrNO Calc'd: C,
55.73; H, 5.04; N, 5.00 Found: C, 55.04; H, 4.80; N, 4.70
[0343] Step 8: 2-Butyl-1-methyl-1H-indole-3-carboxylic acid
(5-bromo-6-methoxy-naphthalen-2-ylmethyl)-methyl-amide. A solution
of 2-butyl-1-methyl-1H-indole-3-carbonyl chloride (13.2 mmol),
prepared in step 4, in 50 mL of methylene chloride was added under
nitrogen dropwise over 30 minutes to a solution of
(5-bromo-6-methoxy-naphthalen-2-ylmethyl- )-methyl-amine (3.70 g,
13.2 mmol), prepared in the previous step, and triethylamine (1.84
mL, 13.2 mmol) in 100 mL of methylene chloride at room temperature.
After the addition the reaction was stirred at room temperature for
17 h (overnight). The reaction was extracted with 1 N HCl. A solid
was suspended between the two layers. The solid was collected by
filtration and dried under reduced pressure to give 219 mg of the
HCl salt of (5-bromo-6-methoxy-naphthalen-2-ylmethyl)-methyl-amine-
. The organic layer of the filtrate was separated from the aqueous
layer and the aqueous layer was extracted two times with methylene
chloride. The combined extracts were dried (MgSO.sub.4) and the
solvent removed under reduced pressure to give
2-butyl-1-methyl-1H-indole-3-carboxylic acid
(5-bromo-6-methoxy-naphthalen-2-ylmethyl)-methyl-amide (6.25 g,
96%) as a brown foam, MS m/z: 493 [M+H].sup.+.
[0344] Elemental Analysis for C.sub.27H.sub.29BrN.sub.2O.sub.2
Calc'd: C, 65.72; H, 5.92; N, 5.68 Found: C, 65.71; H, 6.13; N,
5.48
[0345] Step 9: 2-Butyl-1-methyl-1H-indole-3-carboxylic acid
(5-bromo-6-hydroxy-naphthalen-2-ylmethyl)-methyl-amide. Boron
tribromide (18.78 mL of a 1 M solutioin in methylene chloride;
18.78 mmol) in 20 mL of methylene chloride was added under nitrogen
dropwise over fifteen minutes to a solution of
2-butyl-1-methyl-1H-indole-3-carboxylic acid
(5-bromo-6-methoxy-naphthalen-2-ylmethyl)-methyl-amide (3.09 g,
6.26 mmol), prepared in the previous step, in 125 mL of methylene
chloride at dry ice-acetone temperature. After the addition the dry
ice-acetone bath was replaced with an ice bath and the stirring
continued for 4 h. Water was added to the reaction at ice bath
temperature. The organic layer was separated and the aqueous layer
extracted three times with methylene chloride. The combined
extracts were dried (MgSO.sub.4) and the solvent removed under
reduced pressure to give 2-butyl-1-methyl-1H-indole-3-carbo- xylic
acid (5-bromo-6-hydroxy-naphthalen-2-ylmethyl)-methyl-amide (3.22
g, 100%) as a brown solid foam, MS m/z: 479 [M+H].sup.+.
[0346] Elemental Analysis for C.sub.26H.sub.27BrN.sub.2O.sub.2
Calc'd: C, 65.14; H, 5.68; N, 5.84 Found: C, 61.87; H, 5.47; N,
5.24
[0347] Step 10: 2-butyl-1-methyl-1H-indole-3-carboxylic acid
(5-bromo-6-cyanomethoxy-naphthalen-2-ylmethyl)-methyl-amide. A
mixture of 2-butyl-1-methyl-1H-indole-3-carboxylic acid
(5-bromo-6-hydroxy-naphthale- n-2-ylmethyl)-methyl-amide (2.09 g,
4.36 mmol), prepared in the previous step, bromoacetonitrile (364
.mu.L, 5.23 mmol) and potassium carbonate (3.01 g, 21.8 mmol) in 50
mL of DMF was stirred under nitrogen at room temperature for 16 h
(overnight). The reaction was partitioned between ethyl acetate and
water. The organic layer was separated, extracted multiple times
with water, dried (MgSO.sub.4) and the solvent removed under
reduced pressure to give 2-butyl-1-methyl-1H-indole-3-carboxylic
acid (5-bromo-6-cyanomethoxy-naphthalen-2-ylmethyl)-methyl-amide
(2.00 g, 88%) as a brown solid foam, MS m/z: 518 [M+H].sup.+.
[0348] Elemental Analysis for C.sub.28H.sub.28BrN.sub.3O.sub.2
Calc'd: C, 64.87; H, 5.44; N, 8.10 Found: C, 64.71; H, 5.54; N,
8.01
[0349] Step 11: 2-Butyl-1-methyl-1H-indole-3-carboxylic acid
[5-bromo-6-(1H-tetrazol-5-ylmethoxy)-naphthalen-2-ylmethyl]-methyl-amide.
A mixture of 2-butyl-1-methyl-1H-indole-3-carboxylic acid
(5-bromo-6-cyanomethoxy-naphthalen-2-ylmethyl)-methyl-amide (1.79
g, 3.45 mmol), prepared in the previous step, sodium azide (673 mg,
10.35 mmol) and ammoniun chloride (554 mg, 10.36 mmol) in 100 mL of
DMF was stirred under nitrogen at 100.degree. C. for 4.25 h. The
reaction was diluted with water, made basic by the addition of 20
mL of 1 N NaOH and extracted multiple times with ethyl acetate. The
aqueous layer was acidified with 40 mL of 1 N HCl. A brown oil
separated. The oil was partitioned between the aqueous layer and
methylene chloride. The organic layer separated and the aqueous
layer was extracted three times with methylene chloride. The
combined extracts were dried (MgSO.sub.4) and the solvent removed
under reduced pressure. The residue was dissolved in 20 mL of 1 N
NaOH and then acidified with 30 mL 1 N HCl. The solid that formed
was collected by filtration, rinsed with water and dried under
reduced pressure to give the title compound (1.75 g, 89%) as an
off-white solid, mp 147-149.degree. C.
[0350] Elemental Analysis for
C.sub.28H.sub.29BrNr.sub.6O.sub.2+0.28 H.sub.2O Calc'd: C, 59.36;
H, 5.26; N, 14.83 Found: C, 55.18; H, 4.81; N, 14.19
EXAMPLE 37
1-Methyl-1H-indole-3-carboxylic acid
[5-bromo-6-(1H-tetrazol-5-ylmethoxy)--
naphthalen-2-ylmethyl]-methyl-amide.
[0351] Step 1: 1-Methyl-1H-indole-3-carbonyl chloride. Oxalyl
chloride (11.86 mL, 136 mmol) was added dropwise to a solution of
1-methyl-1H-indole-3-carboxylic acid (4.76 g, 27 mmol) in 100 mL of
methylene chloride. A rapid evolution of gas was observed. The
reaction stirred at room temperature for 17 h (overnight). The
solvent was removed under reduced pressure to give a pink solid To
remove any excess oxalyl chloride the solid was dissolved in
benzene and the solvent removed under reduced pressure to give
1-methyl-1H-indole-3-carbonyl chloride which was immediately used
in step 2 without additional purification.
[0352] Step 2: 1-Methyl-1H-indole-3-carboxylic acid
(5-bromo-6-methoxy-naphthalen-2-ylmethyl)-methyl-amide. A solution
of 1-methyl-1H-indole-3-carbonyl chloride (27 mmol), prepared in
the previous step, in 50 mL of methylene chloride was added
dropwise under nitrogen over 1.5 h to a solution of
(5-bromo-6-methoxy-naphthalen-2-ylme- thyl)-methyl-amide (7.56 g,
27 mmol), prepared in step 7 of Example 36, and triethylamine (3.76
mL, 27 mmol) in 200 mL of methylene chloride at room temperature.
The solution was stirred at room temperature for 22 h (overnight).
The reaction was extracted with 1N HCl. The aqueous layer was
separated and extracted two additional times with methylene
chloride. The organic extracts were combined, dried (MgSO.sub.4)
and the solvent removed under reduced pressure to give 11.52 g of
an off white solid. The solid was recrystallized from methylene
chloride-isopropanol. Off-white crystals were collected by
filtration and dried under reduced pressure to give
1-methyl-1H-indole-3-carboxylic acid
(5-bromo-6-methoxy-naphthalen-2- -ylmethyl)-methyl-amide (9.3389 g,
79%) as an off white solid, mp 168-169.degree. C.
[0353] Elemental Analysis for C.sub.23H.sub.21BrN.sub.2O.sub.2
Calc'd: C, 63.17; H, 4.84; N, 6.41 Found: C, 62.81; H, 4.62; N,
6.27
[0354] Step 3: 1-Methyl-1H-indole-3-carboxylic acid
(5-bromo-6-hydroxy-naphthalen-2-ylmethyl)-methyl-amide. A solution
of 1.0 M boron tribromide in methylene chloride (55.0 mL, 54.9
mmol) in 50 mL of methylene chloride was added under nitrogen
dropwise over 1.5 h to a solution of
1-methyl-1H-indole-3-carboxylic acid (5-bromo-6-methoxy-napht-
halen-2-ylmethyl)-methyl-amide (8.0 g, 18.3 mmol), prepared in the
previous step, in 300 mL of methylene chloride at dry ice-acetone
temperature. The dry ice-acetone bath was replaced with an ice bath
immediately after the addition. The reaction stirred at ice bath
temperature for 2 h. At ice bath temperature, the reaction was
quenched by the dropwise with water. The reaction was partitioned
between methylene chloride and water. A solid formed in the organic
layer and was collected by filtration. The solid was dried under
reduced pressure to give 1-methyl-1H-indole-3-carboxylic acid
(5-bromo-6-hydroxy-naphthalen-2- -ylmethyl)-methyl-amide (6.5359 g,
84%) as a white solid, mp 189-190.degree. C.
[0355] Elemental Analysis for C.sub.22H.sub.19BrN.sub.2O.sub.2
Calc'd: C, 62.42; H, 4.52; N, 6.62 Found: C, 59.60; H, 4.18; N,
6.19
[0356] Step 4: 1-Methyl-1H-indole-3-carboxylic acid
(5-bromo-6-cyanomethoxy-naphthalen-2-ylmethyl)-methyl-amide. A
mixture of 1-methyl-1H-indole-3-carboxylic acid
(5-bromo-6-hydroxy-naphthalen-2-ylme- thyl)-methyl-amide (2.0 g,
4.72 mmol), prepared in the previous step, potassium carbonate
(3.26 g, 23.6 mmol) and bromoacetonitrile (0.39 mL, 5.67 mmol) in
60 mL of DMF was stirred under nitrogen at room temperature for 24
h (overnight). The reaction was partitioned between ethyl acetate
and water. The organic layer was separated, extracted five times
with water, dried (MgSO.sub.4) and the solvent removed under
reduced pressure to give 1-methyl-1H-indole-3-carboxylic acid
(5-bromo-6-cyanomethoxy-naph- thalen-2-ylmethyl)-methyl-amide (2.06
g, 94.5%) as a tan solid, mp 148-150.degree. C.
[0357] Elemental Analysis for C.sub.24H.sub.20BrN.sub.3O.sub.2
Calc'd: C, 62.35; H, 4.36; N, 9.09 Found: C, 62.03; H, 4.28; N,
8.98
[0358] Step 5: 1-Methyl-1H-indole-3-carboxylic acid
[5-bromo-6-(1H-tetrazol-5-ylmethoxy)-naphthalen-2-ylmethyl]-methyl-amide.
A mixture of 1-methyl-1H-indole-3-carboxylic acid
(5-bromo-6-cyanomethoxy- -naphthalen-2-ylmethyl)-methyl-amide (1.0
g, 2.0 mmol), prepared in the previous step, sodium azide (0.32 g,
6.0 mmol) and ammonium chloride (0.39 g, 6.0 mmol) in 15 mL of DMF
was stirred under nitrogen at 100.degree. C. for 6 h. The reaction
was partitioned between ethyl acetate and water. The aqueous layer
was made basic by the addition of 1 N NaOH. The organic layer was
separated and the aqueous layer extracted five times with ethyl
acetate. The aqueous layer was then acidified with 1N HCl. After 2
h a white solid had precipitated from solution. The solid was
collected by filtration and dried under reduced pressure to give
the title compound (0.8460 g, 84%) as an off-white solid, mp
227-228.degree. C.
[0359] Elemental Analysis for C.sub.24H.sub.21BrN.sub.6O.sub.2+0.17
H.sub.2O Calc'd: C, 56.70; H, 4.23; N, 16.53 Found: C, 56.64; H,
4.21; N, 16.47
EXAMPLE 38
5-(3,5-Dichloro-phenoxy)-furan-2-carboxylic acid
[5-bromo-6-(1H-tetrazol-5-
-ylmethoxy)-naphthalen-2-ylmethyl]-methyl-amide.
[0360] Step 1: 5-(3,5-Dichloro-phenoxy)-furan-2-carboxylic acid
(5-bromo-6-methoxy-naphthalen-2-ylmethyl)-methyl-amide. In the same
manner as described in step 2 of Example 37, and after
recrystallization of the crude product from isopropanol,
5-(3,5-dichloro-phenoxy)-furan-2-c- arboxylic acid
(5-bromo-6-methoxy-naphthalen-2-ylmethyl)-methyl-amide (4.2757 g,
54%) was isolated as a tan solid, mp 115-117.degree. C.
[0361] Elemental Analysis for C.sub.24H.sub.18BrCl.sub.2NO.sub.4
Calc'd: C, 53.84; H, 3.39; N, 2.62 Found: C, 53.70; H, 3.20; N,
2.50
[0362] Step 2: 5-(3,5-Dichloro-phenoxy)-furan-2-carboxylic acid
(5-bromo-6-hydroxy-naphthalen-2-ylmethyl)-methyl-amide. In the same
manner as described in step 3 of Example 37, with the exception
that the reaction was partitioned between methylene chloride and
water and no solid formed in either layer. The aqueous layer was
separated and extracted two times with methylene chloride. The
organic extracts were combined, dried (MgSO.sub.4) and the solvent
removed under reduced pressure to give
5-(3,5-dichloro-phenoxy)-furan-2-carboxylic acid
(5-bromo-6-hydroxy-naphthalen-2-ylmethyl)-methyl-amide (3.45 g,
89%) as an off white foam, MS m/z: 520 [M+H]+.
[0363] Elemental Analysis for C.sub.23H.sub.16BrCl.sub.2NO.sub.4
Calc'd: C, 53.00; H, 3.09; N, 2.69 Found: C, 51.86; H, 2.77; N,
2.55
[0364] Step 3: 5-(3,5-Dichloro-phenoxy)-furan-2-carboxylic acid
(5-bromo-6-cyanomethoxy-naphthalen-2-ylmethyl)-methyl-amide.
Prepared in the same manner as described in step 4 of Example 37.
The crude oil was chromatographed on 200 g of silica gel (230-400
mesh) using 0-5% ethyl acetate in methylene chloride as the eluent.
Isolation of the desired material gave
5-(3,5-dichloro-phenoxy)-furan-2-carboxylic acid
(5-bromo-6-cyanomethoxy-naphthalen-2-ylmethyl)-methyl-amide (1.2365
g, 58%) as a white foam, MS m/z: 559 [M+H]+.
[0365] Elemental Analysis for
C.sub.25H.sub.17BrCl.sub.2N.sub.2O.sub.4 Calc'd: C, 53.60; H, 3.06;
N, 5.00 Found: C, 53.47; H, 3.07; N, 4.85
[0366] Step 4: 5-(3,5-Dichloro-phenoxy)-furan-2-carboxylic acid
[5-bromo-6-(1H-tetrazol-5-ylmethoxy)-naphthalen-2-ylmethyl]-methyl-amide.
In the same manner as described in step 5 of Example 37 the title
compound (0.6573 g, 54%) was isolated as a tan foam, MS m/z: 602
[M+H]+.
[0367] Elemental Analysis for
C.sub.25H.sub.18BrCl.sub.2N.sub.5O.sub.4+0.1- 4 H.sub.2O Calc'd: C,
49.57; H, 3.04; N, 11.56 Found: C, 49.31; H, 3.18; N, 11.48
EXAMPLE 39
3-Butyl-benzofuran-2-carboxylic acid
[5-bromo-6-(1H-tetrazol-5-ylmethoxy)--
naphthalen-2-ylmethyl]-methyl-amide.
[0368] Step 1: 3-Butyl-benzofuran-2-carbonyl chloride. Oxalyl
Chloride (3.86 mL, 44.2 mmol) was added under nitrogen at room
temperature to a solution of 3-butyl-benzofuran-2-carboxylic acid
(1.93 g, 8.84 mmol) in 60 mL of methylene chloride. After the
addition a catalytic amount of DMF (10 .mu.L) was added and the
reaction was stirred at room temperature for 2 h. The solvent was
removed under reduced pressure. To remove the excess oxalyl
chloride the residue was dissolved in benzene and the solvent
removed under reduced pressure to give
3-butyl-benzofuran-2-carbonyl chloride, which was immediately used
in step 2 without additional purification.
[0369] Step 2: 3-Butyl-benzofuran-2-carboxylic acid
(5-bromo-6-methoxy-naphthalen-2-ylmethyl)-methyl-amide. A solution
of 3-butyl-benzofuran-2-carbonyl chloride (9.0 mmol), prepared in
the previous step, in 50 mL of methylene chloride was added under
nitrogen dropwise over 2 h to a solution of
(5-bromo-6-methoxy-naphthalen-2-ylmeth- yl)-methyl-amine (2.52 g,
9.0 mmol), prepared in step 7 of Example 36, and triethylamine
(1.26 mmol, 9.0 mmol) in 250 mL of methylene chloride at room
temperature. After the addition the reaction was stirred at room
temperature overnight. The reaction was extracted with 1 N HCl, 5%
NaHCO.sub.3, dried (MgSO.sub.4) and the solvent removed under
reduced pressure to 4.13 g of a residue. Purification of the
residue on 500 g of silica gel (230-400 mesh) using 90%
hexane-methylene chloride to 5% EtOAc-methylene chloride as the
eluents gave 3-butyl-benzofuran-2-carboxy- lic acid
(5-bromo-6-methoxy-naphthalen-2-ylmethyl)-methyl-amide as a clear
oil, MS m/z: 480 [M+H].sup.+.
[0370] Elemental Analysis for C.sub.26H.sub.26BrNO.sub.3 Calc'd: C,
65.01; H, 5.46; N, 2.92 Found: C, 64.23; H, 5.30; N, 2.90
[0371] Step 3: 3-Butyl-benzofuran-2-carboxylic acid
(5-bromo-6-hydroxy-naphthalen-2-ylmethyl)-methyl-amide. In the same
manner as described in step 9 of Example 36,
3-butyl-benzofuran-2-carboxy- lic acid
(5-bromo-6-hydroxy-naphthalen-2-ylmethyl)-methyl-amide (1.89 g,
97%) was isolated as a brown solid, mp 53-56.degree. C.
[0372] Elemental Analysis for C.sub.25H.sub.24BrNO.sub.3 Calc'd: C,
64.38; H, 5.19; N, 3.00 Found: C, 63.69; H, 5.08; N, 2.87
[0373] Step 4: 3-Butyl-benzofuran-2-carboxylic acid
(5-bromo-6-cyanomethoxy-naphthalen-2-ylmethyl)-methyl-amide. In the
same manner as described in step 10 of Example 36,
3-butyl-benzofuran-2-carbox- ylic acid
(5-bromo-6-cyanomethoxy-naphthalen-2-ylmethyl)-methyl-amide was
isolated as a brown oil, MS m/z: 505 [M+H].sup.+.
[0374] Elemental Analysis for C.sub.27H.sub.25BrN.sub.2O.sub.3
Calc'd: C, 64.16; H, 4.99; N, 5.54 Found: C, 63.19; H, 5.02; N,
5.73
[0375] Step 5: 3-Butyl-benzofuran-2-carboxylic acid
[5-bromo-6-(1H-tetrazol-5-ylmethoxy)-naphthalen-2-ylmethyl]-methyl-amide.
A mixture of 3-butyl-benzofuran-2-carboxylic acid
(5-bromo-6-cyanomethoxy- -naphthalen-2-ylmethyl)-methyl-amide (1.90
g, 3.77 mmol), prepared in the previous step, sodium azide (735 mg,
11.3 mmol) and ammonium chloride (607 mg, 11.3 mmol) in 50 mL of
DMF was stirred under nitrogen at 100.degree. C. for 5 h. By TLC
starting material remained. An additional 732 mg (11.3 mmol) of
sodium azide was added and the stirring continued at 100.degree. C.
for 2 h. The reaction was diluted with 50 mL of water, made basic
by the addition of 1 N NaOH and then extracted three times with
ethyl acetate. The aqueous layer was acidified with 1 N HCl and the
solid that formed was collected by filtration and dried under
reduced pressure to give the title compound (1.17 g, 57%) as a
light brown solid, mp 180-183.degree. C.
[0376] Elemental Analysis for C.sub.27H.sub.26BrN.sub.5O.sub.3+0.01
H.sub.2O Calc'd: C, 59.11; H, 4.78; N, 12.77 Found: C, 58.93; H,
4.73; N, 12.94
EXAMPLE 40
2-Benzyl-3-(1-bromo-6-{[(3-butyl-benzofuran-2-carbonyl)-methyl-amino]-meth-
yl}-naphthalen-2-yloxy)-propionic acid.
[0377] Step 1:
2-Benzyl-3-(1-bromo-6-{[(3-butyl-benzofuran-2-carbonyl)-met-
hyl-amino]-methyl}-naphthalen-2-yloxy)-propionic acid methyl ester.
A mixture of 3-butyl-benzofuran-2-carboxylic acid
(5-bromo-6-hydroxy-naphth- alen-2-ylmethyl)-methyl-amide (1.03 g,
2.20 mmol), prepared in step 3 of Example 39,
3-phenyl-2-trifluoromethanesulfonyloxy-propionic acid methyl ester
(1.04 g, 3.32 mmol), prepared in step 2 of Example 7, and cesium
carbonate (1.44 g, 4.41 mmol) in 60 mL of acetone was stirred under
nitrogen at room temperature for 8 h. The acetone was removed under
reduced pressure and the residue partitioned between ethyl acetate
and water. The aqueous layer was separated and extracted three
times with ethyl acetate. The combined organic extracts were dried
(MgSO.sub.4) and the solvent removed under reduced pressure to give
1.63 g of an oil. Purification of the oil on a 90 g KP-SIL 60
.DELTA. Biotage column using 1:1 hexane-methylene chloride as the
eluent gave 2-benzyl-3-(1-bromo-6-{[-
(3-butyl-benzofuran-2-carbonyl)-methyl-amino]-methyl}-naphthalen-2-yloxy)--
propionic acid methyl ester (869 mg, 63%) as a clear oil, MS m/z:
628 [M+H].sup.+.
[0378] Elemental Analysis for C.sub.35H.sub.34BrNO.sub.5 Calc'd: C,
66.88; H, 5.45; N, 2.23 Found: C, 66.95; H, 5.51; N, 2.22
[0379] Step 2:
2-Benzyl-3-(1-bromo-6-{[(3-butyl-benzofuran-2-carbonyl)-met-
hyl-amino]-methyl}-naphthalen-2-yloxy)-propionic acid. A mixture of
1 N NaOH (2.5 mL, 2.5 mmol) and
2-benzyl-3-(1-bromo-6-{[(3-butyl-benzofuran-2-
-carbonyl)-methyl-amino]-methyl}-naphthalen-2-yloxy)-propionic acid
methyl ester (769 mg, 1.22 mmol), prepared in the previous step, in
30 mL of methanol plus 2 mL of water was stirred under nitrogen at
room temperature for 6 h. By TLC starting material remained. An
additional 2.5 mL (2.5 mmol) of 1 N NaOH was added and the stirring
continued at room temperature overnight. 1 N HCl (5.1 mL, 5.1 mmol)
was added and the reaction concentrated under reduced pressure to
remove the methanol. The solid that formed was collected by
filtration and dried under reduced pressure to give the title
compound (318 mg, 42%) as a white solid, mp 64-68.degree. C.
[0380] Elemental Analysis for C.sub.34H.sub.32BrNO.sub.5+0.45
H.sub.2O Calc'd: C, 65.59; H, 5.53; N, 2.25 Found: C, 64.75; H,
5.21; N, 2.15
EXAMPLE 41
3-Methyl-benzofuran-2-carboxylic acid
[5-bromo-6-(1H-tetrazol-5-ylmethoxy)-
-naphthalen-2-ylmethyl]-methyl-amide.
[0381] Step 1: 3-Methyl-benzofuran-2-carbonyl chloride. In the same
manner as described in step 1 of Example 39,
3-methyl-benzofuran-2-carbonyl chloride was isolated and
immediately used in step 2 without additional purification.
[0382] Step 2: 3-Methyl-benzofuran-2-carboxylic acid
(5-bromo-6-methoxy-naphthalen-2-ylmethyl)-methyl-amide. In the same
manner as described in step 2 of Example 39,
3-methyl-benzofuran-2-carbox- ylic acid
(5-bromo-6-methoxy-naphthalen-2-ylmethyl)-methyl-amide (8.17 g,
92%) was isolated as a white solid, mp138-140.degree. C.
[0383] Elemental Analysis for C.sub.23H.sub.20BrNO.sub.3 Calc'd: C,
63.03; H, 4.60; N, 3.20 Found: C, 62.68; H, 4.21; N, 3.13
[0384] Step 3: 3-Methyl-benzofuran-2-carboxylic acid
(5-bromo-6-hydroxy-naphthalen-2-ylmethyl)-methyl-amide. In the same
manner as described in step 9 of Example 36,
3-methyl-benzofuran-2-carbox- ylic acid
(5-bromo-6-hydroxy-naphthalen-2-ylmethyl)-methyl-amide (5.81 g,
100%) was isolated as a brown foam, MS m/z: 424 [M+H].sup.+.
[0385] Elemental Analysis for C.sub.22H.sub.18BrNO.sub.3 Calc'd: C,
62.28; H, 4.28; N, 3.30 Found: C, 60.03; H, 4.26; N, 3.04
[0386] Step 4: 3-Methyl-benzofuran-2-carboxylic acid
(5-bromo-6-cyanomethoxy-naphthalen-2-ylmethyl)-methyl-amide. In the
same manner as described in step 10 of Example 36,
3-methyl-benzofuran-2-carbo- xylic acid
(5-bromo-6-cyanomethoxy-naphthalen-2-ylmethyl)-methyl-amide (2.67
g, 98%) was isolated as a brown solid, mp 35-38.degree. C.
[0387] Elemental Analysis for C.sub.24H.sub.19BrN.sub.2O.sub.3
Calc'd: C, 62.22; H, 4.13; N, 6.05 Found: C, 61.78; H, 4.02; N,
5.85
[0388] Step 5: 3-Methyl-benzofuran-2-carboxylic acid
[5-bromo-6-(1H-tetrazol-5-ylmethoxy)-naphthalen-2-ylmethyl]-methyl-amide.
A mixture of 3-methyl-benzofuran-2-carboxylic acid
(5-bromo-6-cyanomethoxy-naphthalen-2-ylmethyl)-methyl-amide (2.039
g, 4.40 mmol), prepared in the previous step, sodium azide (846 mg,
13.0 mmol) and ammonium chloride (695 mg, 13.0 mmol) in 60 mL of
DMF was stirred under nitrogen at 100.degree. C. for 6 h. The
reaction was diluted with water, made basic by the addition of 1 N
NaOH and extracted three times with ethyl acetate. The aqueous
layer was acidified with 1 N HCl, which caused an oil to
precipitate. The aqueous layer was decanted from the oil. Water was
added to the oil, which caused it to solidify. The solid was
collected by filtration, rinsed with water and dried under reduced
pressure to give the title compound as a white solid, mp
164-166.degree. C.
[0389] Elemental Analysis for C.sub.24H.sub.20BrN.sub.5O.sub.3
Calc'd: C, 56.93; H, 3.98; N, 13.83 Found: C, 56.43; H, 3.86; N,
13.75
EXAMPLE 42
Sodium;
2-benzyl-3-(1-bromo-6-{[methyl-(3-methyl-benzofuran-2-carbonyl)-am-
ino]-methyl}-naphthalen-2-yloxy)-propionate.
[0390] Step 1:
2-Benzyl-3-(1-bromo-6-{[methyl-(3-methyl-benzofuran-2-carbo-
nyl)-amino]-methyl}-naphthalen-2-yloxy)-propionic acid methyl
ester. In the same manner as described in step 1 of Example 40, and
replacing 3-butyl-benzofuran-2-carboxylic acid
(5-bromo-6-hydroxy-naphthalen-2-ylme- thyl)-methyl-amide with
3-methyl-benzofuran-2-carboxylic acid
(5-bromo-6-hydroxy-naphthalen-2-ylmethyl)-methyl-amide, prepared in
step 3 of Example 41,
2-benzyl-3-(1-bromo-6-{[methyl-(3-methyl-benzofuran-2-ca-
rbonyl)-amino]-methyl}-naphthalen-2-yloxy)-propionic acid methyl
ester (3.31 g, 97%) was isolated as a clear oil, MS m/z: 586
[M+H].sup.+.
[0391] Elemental Analysis for C.sub.32H.sub.28BrNO.sub.5 Calc'd: C,
65.54; H, 4.81; N, 2.39 Found: C, 66.25; H, 4.65; N, 1.67
[0392] Step 2: Sodium;
2-benzyl-3-(1-bromo-6-{[methyl-(3-methyl-benzofuran-
-2-carbonyl)-amino]-methyl}-naphthalen-2-yloxy)-propionate. A
mixture of 1 N NaOH (12 mL, 12 mmol) and
2-benzyl-3-(1-bromo-6-{[methyl-(3-methyl-benz-
ofuran-2-carbonyl)-amino]-methyl}-naphthalen-2-yloxy)-propionic
acid methyl ester (3.31 g, 5.80 mmol), prepared in the previous
step, in 120 mL of methanol plus 15 mL of water was stirred under
nitrogen at room temperature overnight. 1 N HCl (13 mL, 13 mmol)
was added and the reaction concentrated under reduced pressure to
remove the methanol. The solid that formed was collected by
filtration and dried under reduced pressure to give the title
compound (2.16 g, 67%) as a white solid, mp 112-114.degree. C.
[0393] Elemental Analysis for C.sub.31H.sub.26BrNO.sub.5Na+0.15
H.sub.2O Calc'd: C, 62.35; H, 4.27; N, 2.35 Found: C, 63.31; H,
4.47; N, 2.30
EXAMPLE 43
3-Methyl-benzofuran-2-carboxylic acid
[5-bromo-6-(1H-tetrazol-5-ylmethoxy)-
-naphthalen-2-ylmethyl]-amide.
[0394] Step 1: 5-Bromo-6-methoxy-naphthalene-2-carbonitrile.
Bromine (7.0 mL, 0.137 mol) in 100 mL of glacial HOAc was added
under nitrogen dropwise over 4 h to a solution of
6-methoxy-naphthalene-2-carbonitrile (25.02 g, 0.137 mol) in 700 mL
of glacial HOAc at room temperature. After the addition the
reaction was stirred at room temperature overnight. The solid that
formed was collected by filtration, rinsed with glacial HOAc and
dried under reduced pressure to give
5-bromo-6-methoxy-naphthalene-2-- carbonitrile (31.35 g, 88%) as a
white solid, mp 177-178.degree. C.
[0395] Elemental Analysis for C.sub.12H.sub.8BrNO Calc'd: C, 54.99;
H, 3.08; N, 5.34 Found: C, 55.16; H, 2.92; N, 5.43
[0396] Step 2: 5-Bromo-6-methoxy-naphthalen-2-ylmethyl-ammonium;
chloride. BH.sub.3-THF (286 mL of a 1.0 molar solution in THF; 286
mmol) was added under nitrogen dropwise over 45 minutes to a
solution of 5-bromo-6-methoxy-naphthalene-2-carbonitrile (25.02 g,
95.4 mmol), prepared in the previous step, in 650 mL of anhydrous
THF at room temperature. After the addition the reaction was
refluxed overnight. The reaction was quenched by the dropwise
addition of 60 mL of 1 N HCl. The solid that precipitated was
collected by filtration and dried under reduced pressure to give
5-bromo-6-methoxy-naphthalen-2-ylmethyl-ammonium- ; chloride (5.34
g, 21%) as a white solid, mp 274-276.degree. C.
[0397] Elemental Analysis for C.sub.12H.sub.12BrNO+HCl+0.71H.sub.2O
Calc'd: C, 45.70; H, 4.61; N, 4.44 Found: C, 45.65; H, 4.60; N,
4.31
[0398] Step 3: 3-Methyl-benzofuran-2-carboxylic acid
(5-bromo-6-methoxy-naphthalen-2-ylmethyl)-amide.
3-Methyl-benzofuran-2-ca- rbonyl chloride (1.23 g, 6.34 mmol),
prepared in step 1 of Example 41, in 30 mL of methylene chloride
was added under nitrogen dropwise to a suspension of
5-bromo-6-methoxy-naphthalen-2-ylmethyl-ammonium; chloride (2.00 g,
6.34 mmol),prepared in the previous step, in 700 mL of anhydrous
pyridine at room temperature. After the addition the reaction was
stirred at room temperature overnight. The reaction was
concentrated under reduced pressure to remove most of the solvent.
The residue was partitioned between 1 N HCl and methylene chloride.
The aqueous layer was separated and extracted two times with
methylene chloride. The combined extracts were dried (MgSO.sub.4)
and the solvent removed under reduced pressure to give 2.37 g of a
residue. Purification of the residue by chromatography on silica
gel gave 3-methyl-benzofuran-2-carboxylic acid
(5-bromo-6-methoxy-naphthalen-2-ylmethyl)-amide (1.60 g, 60%) as a
white solid, mp 154-156.degree. C.
[0399] Elemental Analysis for C.sub.22H.sub.18BrNO.sub.3 Calc'd: C,
62.28; H, 4.28; N, 3.30 Found: C, 62.14; H, 4.13; N, 3.22
[0400] Step 4: 3-Methyl-benzofuran-2-carboxylic acid
(5-bromo-6-hydroxy-naphthalen-2-ylmethyl)-amide. In the same manner
as described in step 3 of Example 37,
3-methyl-benzofuran-2-carboxylic acid
(5-bromo-6-hydroxy-naphthalen-2-ylmethyl)-amide (1.34 g, 91%) was
isolated as a white solid, mp 194-197.degree. C.
[0401] Elemental Analysis for C.sub.21H.sub.16BrNO.sub.3 Calc'd: C,
61.48; H, 3.93; N, 3.41 Found: C, 61.48; H, 3.90; N, 3.14
[0402] Step 5: 3-Methyl-benzofuran-2-carboxylic acid
(5-bromo-6-cyanomethoxy-naphthalen-2-ylmethyl)-amide. In the same
manner as described in step 10 of Example 36,
3-methyl-benzofuran-2-carboxylic acid
(5-bromo-6-cyanomethoxy-naphthalen-2-ylmethyl)-amide (1.25 g, 96%)
was isolated as a yellow solid, mp 194-197.degree. C.
[0403] Elemental Analysis for C.sub.23H.sub.17BrN.sub.2O.sub.3
Calc'd: C, 61.48; H, 3.81; N, 6.23 Found: C, 61.69; H, 3.89; N,
6.01
[0404] Step 6: 3-Methyl-benzofuran-2-carboxylic acid
[5-bromo-6-(1H-tetrazol-5-ylmethoxy)-naphthalen-2-ylmethyl]-amide.
A mixture of 3-methyl-benzofuran-2-carboxylic acid
(5-bromo-6-cyanomethoxy-- naphthalen-2-ylmethyl)-amide (1.14 g,
2.54 mmol), prepared in the previous step, sodium azide (492 mg,
7.57 mmol) and ammonium chloride (406 mg, 7.59 mmol) in 50 mL of
DMF was stirred under nitrogen at 100.degree. C. for 5 h. By TLC
starting material remained. An additional 494 mg (7.60 mmol) of
sodium azide was added and the stirring continued at 100.degree. C.
for 2 h. The reaction was diluted with water, made basic by the
addition of 1 N NaOH and extracted three times with ethyl acetate.
The aqueous layer was acidified with 1 N HCl and the solid that
precipitated was collected by filtration and dried under reduced
pressure to give the title compound (987 mg, 79%) as a light brown
solid, mp 212-215.degree. C.
[0405] Elemental Analysis for C.sub.23H.sub.18BrN.sub.5O.sub.3+0.18
H.sub.2O Calc'd: C, 55.74; H, 3.73; N, 14.13 Found: C, 55.86; H,
3.72; N, 14.13
EXAMPLE 44
2-(1-Bromo-6-{[(3-methyl-benzofuran-2-carbonyl)-amino]-methyl}-naphthalen--
2-yloxy)-3-phenyl-propionic acid
[0406] Step 1:
2-(1-Bromo-6-{[(3-methyl-benzofuran-2-carbonyl)-amino]-meth-
yl}-naphthalen-2-yloxy)-3-phenyl-propionic acid methyl ester. In
the same manner as described in step 1 of Example 40, and replacing
3-butyl-benzofuran-2-carboxylic acid
(5-bromo-6-hydroxy-naphthalen-2-ylme- thyl)-methyl-amide with
3-methyl-benzofuran-2-carboxylic acid
(5-bromo-6-hydroxy-naphthalen-2-ylmethyl)-amide, prepared in step 4
of Example 43,
2-(1-bromo-6-{[(3-methyl-benzofuran-2-carbonyl)-amino]-methyl-
}-naphthalen-2-yloxy)-3-phenyl-propionic acid methyl ester (1.76 g,
100%) was isolated as an off-white solid, mp 129-133.degree. C.
[0407] Elemental Analysis for C.sub.31H.sub.26BrNO.sub.5 Calc'd: C,
65.04; H, 4.58; N, 2.45 Found: C, 64.28: H, 4.70; N, 2.25
[0408] Step 2:
2-(1-Bromo-6-{[(3-methyl-benzofuran-2-carbonyl)-amino]-meth-
yl}-naphthalen-2-yloxy)-3-phenyl-propionic acid. A mixture of 1 N
NaOH (5 mL, 5 mmol) and
2-(1-bromo-6-{[(3-methyl-benzofuran-2-carbonyl)-amino]-me-
thyl}-naphthalen-2-yloxy)-3-phenyl-propionic acid methyl ester
(1.58 g, 2.76 mmol), prepared in the previous step, in 200 mL of
methanol plus 5 mL of water was stirred under nitrogen at room
temperature overnight and then at 60.degree. C. for 6 h. 1 N HCl
(6.2 mL, 6.2 mmol) was added and the reaction concentrated under
reduced pressure to remove the methanol. The solid that
precipitated was collected by filtration and dried under reduced
pressure to give the title compound as an off-white solid, mp
110-113.degree. C.
[0409] Elemental Analysis for C.sub.30H.sub.24BrNO.sub.5+0.42
H.sub.2O Calc'd: C, 63.66; H, 4.42; N, 2.47 Found: C, 63.47; H,
4.30; N, 2.40
EXAMPLE 45
3-Phenethyl-benzofuran-2-carboxylic acid
[5-bromo-6-(1H-tetrazol-5-ylmetho-
xy)-naphthalen-2-ylmethyl]-methyl-amide.
[0410] Step 1: 3-Phenethyl-benzofuran-2-carboxylic acid.
3-Methyl-benzofuran-2-carboxylic acid (9.99 g, 56.7 mmol) in 150 mL
of anhydrous THF was added under nitrogen dropwise to a solution of
lithium diisopropylamide (60 mL of a 2.0 M solution in
heptane/THF/ethylbenzene; 120 mmol) in 350 mL of anhydrous THF at
-10.degree. C. After the addition was complete the reaction was
stirred at -10.degree. C. for approximately 10 minutes. Benzyl
bromide (13.5 mL, 113 mmol) was then added dropwise to the
reaction. After the addition the reaction was allowed to warm to
room temperature and then stirred at room temperature for 2 h. The
reaction was acidified by the addition of 1 N HCl and then
concentrated under reduced pressure to remove the THF. The residue
was partitioned between 1 N HCl and methylene chloride. The aqueous
layer was separated and extracted two times with methylene
chloride. The combined extracts were dried (MgSO.sub.4) and the
solvent removed under reduced pressure. The residue was
recrystallized from ethyl acetate to give
3-phenethyl-benzofuran-2-carboxylic acid (1.62 g, 11 %) as a white
solid, mp 169-172.degree. C.
[0411] Elemental Analysis for C.sub.17H.sub.14O.sub.3 Calc'd: C,
76.68; H, 5.30; N, 0.00 Found: C, 76.18; H, 5.27; N, 0.02
[0412] Step 2: 3-Phenethyl-benzofuran-2-carboxyl chloride. In the
same manner as described in step 1 of Example 39,
3-Phenethyl-benzofuran-2-car- boxyl chloride (1.65 g, 100%) was
isolated and immediately used in step 3 without additional
purification.
[0413] Step 3: 3-Phenylethyl-benzofuran-2-carboxylic acid
(5-bromo-6-methoxy-naphthalen-2-ylmethyl)-methyl-amide.
3-Phenethyl-benzofuran-2-carboxyl chloride (1.65 g, 5.80 mmol),
prepared in the previous step, in 60 mL of methylene chloride was
added under nitrogen to a mixture of
(5-bromo-6-methoxy-naphthalen-2-ylmethyl)-methyl- -amine (1.62 g,
5.80 mmol), prepared in step 7 of Example 36, and triethylamine
(815 .mu.L, 5.80 mmol) in 80 mL of methylene chloride at room
temperature. After the addition the reaction was stirred at room
temperature overnight. The reaction was extracted with 1 N HCl, 5%
NaHCO.sub.3, dried (MgSO.sub.4) and the solvent removed under
reduced pressure to give 2.89 g of a light brown foam. Purification
of the foam on a 120 g KP-SIL 60 .DELTA. Bioitage column using 4:1
hexane:ethyl acetate as the eluent gave
3-phenylethyl-benzofuran-2-carboxylic acid
(5-bromo-6-methoxy-naphthalen-2-ylmethyl)-methyl-amide (2.72 g,
89%) as a white solid, mp 54-57.degree. C.
[0414] Elemental Analysis for C.sub.30H.sub.26BrNO.sub.3 Calc'd: C,
68.19; H, 4.96; N, 2.65 Found: C, 67.96; H, 4.85; N, 2.51
[0415] Step 4: 3-Phenylethyl-benzofuran-2-carboxylic acid
(5-bromo-6-hydroxy-naphthalen-2-ylmethyl)-methyl-amide. In the same
manner as described in step 3 of Example 37,
3-phenylethyl-benzofuran-2-c- arboxylic acid
(5-bromo-6-hydroxy-naphthalen-2-ylmethyl)-methyl-amide (2.48 g,
97%) was isolated as a brown solid, mp 108-110.degree. C.
[0416] Elemental Analysis for C.sub.29H.sub.24BrNO.sub.3 Calc'd: C,
67.71; H, 4.70; N, 2.72 Found: C, 65.97; H, 4.36; N, 2.55
[0417] Step 5: 3-Phenylethyl-benzofuran-2-carboxylic acid
(5-bromo-6-cyanomethoxy-naphthalen-2-ylmethyl)-methyl-amide. In the
same manner as described in step 10 of Example 36,
3-phenylethyl-benzofuran-2-- carboxylic acid
(5-bromo-6-cyanomethoxy-naphthalen-2-ylmethyl)-methyl-amid- e (2.54
g, 99%) was isolated as a dark green solid, mp 51-55.degree. C.
[0418] Elemental Analysis for C.sub.31H.sub.25BrN.sub.2O.sub.3
Calc'd: C, 67.28; H, 4.55; N, 5.06 Found: C, 66.46; H, 4.48; N,
5.52
[0419] Step 6: 3-Phenethyl-benzofuran-2-carboxylic acid
[5-bromo-6-(1H-tetrazol-5-ylmethoxy)-naphthalen-2-ylmethyl]-methyl-amide.
A mixture of 3-phenylethyl-benzofuran-2-carboxylic acid
(5-bromo-6-cyanomethoxy-naphthalen-2-ylmethyl)-methyl-amide (2.29
g, 4.15 mmol), prepared in the previous step, sodium azide (808 mg,
12.4 mmol) and ammonium chloride (668 mg, 12.5 mmol) in 50 mL of
DMF was stirred under nitrogen at 100.degree. C. for 5 h. By TLC
starting material remained. An additional 801 mg (12.3 mmol) of
sodium azide was added and the reaction stirred at 100.degree. C.
overnight. The reaction was diluted with 50 mL of water, made basic
by the addition of 1 N NaOH and extracted three times with ethyl
acetate. The aqueous layer was acidified with 1 N HCl. An oil
precipitated. The aqueous layer was decanted and the oil
partitioned between methylene chloride and water. The organic layer
was separated, dried (MgSO.sub.4) and the solvent removed under
reduced pressure to give the title compound as a light brown solid,
mp 56-59.degree. C.
[0420] Elemental Analysis for C.sub.31H.sub.26BrN.sub.5O.sub.3+0.07
H.sub.2O Calc'd: C, 62.29; H, 4.41; N, 11.72 Found: C, 61.47; H,
4.19; N, 11.75
EXAMPLE 46
2-(1-Bromo-6-{[methyl-(3-phenethyl-benzofuran-2-carbonyl)-amino]-methyl}-n-
aphthalen-2-yloxy)-3-phenyl-propionic acid
[0421] Step 1:
2-(1-Bromo-6-{[methyl-(3-phenethyl-benzofuran-2-carbonyl)-a-
mino]-methyl}-naphthalen-2-yloxy)-3-phenyl-propionic acid methyl
ester. In the same manner as described in step 1 of Example 40, and
replacing 3-butyl-benzofuran-2-carboxylic acid
(5-bromo-6-hydroxy-naphthalen-2-ylme- thyl)-methyl-amide with
3-phenylethyl-benzofuran-2-carboxylic acid
(5-bromo-6-hydroxy-naphthalen-2-ylmethyl)-methyl-amide, prepared in
step 4 of Example 45,
2-(1-bromo-6-{[methyl-(3-phenethyl-benzofuran-2-carbonyl-
)-amino]-methyl}-naphthalen-2-yloxy)-3-phenyl-propionic acid methyl
ester (1.84 g, 93%) was isolated as a white solid, mp 29-32.degree.
C.
[0422] Elemental Analysis for C.sub.39H.sub.34BrNO.sub.5 Calc'd: C,
69.23; H, 5.06; N, 2.07 Found: C, 69.10; H, 5.06; N, 1.85
[0423] Step 2:
2-(1-Bromo-6-{[methyl-(3-phenethyl-benzofuran-2-carbonyl)-a-
mino]-methyl}-naphthalen-2-yloxy)-3-phenyl-propionic acid. A
mixture of 1 N NaOH (5 mL, 5 mmol) and
2-(1-bromo-6-{[methyl-(3-phenethyl-benzofuran-2-
-carbonyl)-amino]-methyl}-naphthalen-2-yloxy)-3-phenyl-propionic
acid methyl ester (1.68 g, 2.49 mmol), prepared in the previous
step, in 110 mL of methanol plus 5 mL of water was stirred under
nitrogen at room temperature overnight. 1 N HCl (50 mL, 50 mmol)
was added and the reaction was concentrated under reduced pressure
to remove the methanol. The solid that formed was collected by
filtration and dried under reduced pressure to give the title
compound (1.20 g, 73%) as a white solid, mp 87-90.degree. C.
[0424] Elemental Analysis for C.sub.38H.sub.32BrNO.sub.5+0.48
H.sub.2O Calc'd: C, 68.00; H, 4.95; N, 2.09 Found: C, 68.39; H,
4.67; N, 2.03
EXAMPLE 47
(1-Bromo-6-{[methyl-(3-phenethyl-benzofuran-2-carbonyl)-amino]-methyl}-nap-
hthalen-2-yloxy)-acetic acid
[0425] Step 1:
(1-Bromo-6-{[methyl-(3-phenethyl-benzofuran-2-carbonyl)-ami-
no]-methyl}-naphthalen-2-yloxy)-acetic acid methyl ester. A mixture
of 3-phenylethyl-benzofuran-2-carboxylic acid
(5-bromo-6-hydroxy-naphthalen-- 2-ylmethyl)-methyl-amide, prepared
in step 4 of Example 45, methyl bromoacetate (260 .mu.L, 2.75 mmol)
and potassium carbonate (1.58 g, 11.96 mmol) in 25 mL of DMF was
stirred under nitrogen at room temperature 16 h (overnight). The
reaction was partitioned between ethyl acetate and water. The
organic layer was separated, extracted multiple times with water,
dried (MgSO.sub.4) and the solvent removed under reduced pressure
to give (1-bromo-6-{[methyl-(3-phenethyl-benzofuran-2-ca-
rbonyl)-amino]-methyl}-naphthalen-2-yloxy)-acetic acid methyl ester
(1.29 g, 96%) as a light brown foam, MS m/z: 586 [M+H].sup.+.
[0426] Elemental Analysis for C.sub.32H.sub.28BrNO.sub.5 Calc'd: C,
65.54; H, 4.81; N, 2.39 Found: C, 64.38; H, 4.68; N, 2.27
[0427] Step 2:
(1-Bromo-6-{[methyl-(3-phenethyl-benzofuran-2-carbonyl)-ami-
no]-methyl}-naphthalen-2-yloxy)-acetic acid. A mixture of 1 N NaOH
(4 mL, 4 mmol) and
(1-bromo-6-{[methyl-(3-phenethyl-benzofuran-2-carbonyl)-amino-
]-methyl}-naphthalen-2-yloxy)-acetic acid methyl ester (1.19 g,
2.02 mmol), prepared in the previous step, in 100 mL of methanol
plus 4 mL of water was stirred under nitrogen at room temperature
overnight. 1 N HCl (4 mL, 4 mmol) was added and the reaction
concentrated under reduced pressure to remove the methanol. The
solid that formed was collected by filtration and dried under
reduced pressure to give the title compound (1.11 g, 96%) as an
off-white solid, mp 119-122.degree. C.
[0428] Elemental Analysis for C.sub.31H.sub.26BrNO.sub.5Na+0.51
H.sub.2O Calc'd: C, 61.68; H, 4.34; N, 2.32 Found: C, 61.85; H,
4.21; N, 2.33
EXAMPLE 48
2-Butyl-benzofuran-3-carboxylic acid
benzyl-[5-bromo-6-(1H-tetrazol-5-ylme- thoxy)-naphthalen-2-yl
methyl]-amide
[0429] Step 1: Benzyl-(6-methoxy-naphthalen-2-ylmethylene)-amine. A
solution of benzylamine (0.57 mL, 5.37 mmol) in 5mL of methylene
chloride was added dropwise under nitrogen over 5 minutes to a
mixture of 6-methoxy-naphthalene-2-carbaldehyde (1.0 g, 5.37 mmol)
and anhydrous MgSO.sub.4 (3 g) in 20 mL of methylene chloride. The
reaction stirred under nitrogen for 24 h (overnight). The
MgSO.sub.4 was removed by filtration and the solvent removed under
reduced pressure to give
benzyl-(6-methoxy-naphthalen-2-ylmethylene)-amine (1.455 g, 98%) as
an off-white solid, mp 115-117.degree. C.
[0430] Elemental Analysis for C.sub.19H.sub.17NO Calc'd: C, 82.88;
H, 6.22; N, 5.09 Found: C, 83.26; H, 6.22; N, 5.04
[0431] Step 2: Benzyl-(6-methoxy-naphthalen-2-ylmethyl)-amine.
Sodium borohydride (0.19 g, 5 mmol) was added in portions under
nitrogen to a solution of
benzyl-(6-methoxy-naphthalen-2-ylmethylene)-amine (1.38 g, 5 mmol),
prepared in the previous step, in 150 mL of absolute ethanol at
room temperature. After the addition the reaction was stirred at
room temperature for 20 h (overnight). The reaction was quenched
with 30 mL of 1 N HCl (pH 2 by litmus paper). The solvent was
removed under reduced pressure to give a solid. The solid was
partitioned between methylene chloride and water. The aqueous layer
was made basic with 1 N NaOH. The aqueous layer was separated and
extracted two times with methylene chloride. The organic extracts
were combined, dried (MgSO.sub.4) and the solvent removed under
reduced pressure to give benzyl-(6-methoxy-naphthal-
en-2-ylmethyl)-amine (1.38 g, 100%) as an off-white solid, mp
45-53.degree. C.
[0432] Elemental Analysis for C.sub.19H.sub.19NO Calc'd: C, 82.28;
H, 6.90; N, 5.05 Found: C, 82.64; H, 6.91; N, 4.97
[0433] Step 3: 6-(Benzylamino-methyl)-naphthalen-2-ol. A mixture of
benzyl-(6-methoxy-naphthalen-2-ylmethyl)-amine (1.3 g, 4.7 mmol),
prepared in the previous step, 65 mL of 48% HBr and 50 mL of
glacial acetic acid was refluxed under nitrogen for 19 h
(overnight). The solvent was removed under reduced pressure to give
a red solid. The solid was suspended in 250 mL of water and heated
until most of the solid dissolved. The mixture was filtered, the
filtrate made basic with sodium bicarbonate and extracted three
times with ethyl acetate. The organic extracts were combined, dried
(MgSO.sub.4) and the solvent removed under reduced pressure to give
6-(benzylamino-methyl)-naphthalen-2-ol (0.76 g, 62%) as a green
solid, mp 120-122.degree. C.
[0434] Elemental Analysis for C.sub.18H.sub.17NO Calc'd: C, 82.10;
H, 6.51; N, 5.32 Found: C, 80.58; H, 6.21; N, 5.22
[0435] Step 4: 2-Butyl-benzofuran-3-carboxylic acid
benzyl-(6-hydroxy-naphthalen-2-ylmethyl)-amide.
2-Butyl-benzofuran-3-carb- onyl-chloride (3 mmol), prepared in step
2 of Example 3, in 25 mL of anhydrous THF was added under nitrogen
dropwise over 1 h to a solution of
6-(benzylamino-methyl)-naphthalen-2-ol (0.71 g, 2.7 mmol), prepared
in the previous step, and triethylamine (0.376 mL, 2.7 mmol) in 75
mL of anhydrous THF at room temperature. After the addition the
reaction was stirred at room temperature for 20 h (overnight). The
solid present was removed by filtration and the filtrate
concentrated under reduced pressure to give a brown oil. The oil
was dissolved in ethyl acetate and extracted with 1 N HCl. The
organic layer was dried (MgSO.sub.4) and the solvent removed under
reduced pressure. Chromatography of the crude oil on 200 g of
silica gel (230-400 mesh) using 0%-5% ethyl acetate in methylene
chloride as the eluent gave 2-butyl-benzofuran-3-carboxylic acid
benzyl-(6-hydroxy-naphthalen-2-ylmethyl)-amide (0.8164 g, 65%) as a
light yellow solid, mp 160-164.degree. C.
[0436] Elemental Analysis for C.sub.31H.sub.29NO.sub.3 Calc'd: C,
80.32; H, 6.31; N, 3.02 Found: C, 80.07; H, 6.34; N, 2.82
[0437] Step 5: 2-Butyl-benzofuran-3-carboxylic acid
benzyl-(5-bromo-6-hydroxy-naphthalen-2-ylmethyl)-amide. Prepared in
the same manner as described in step 3 of Example 32,
2-butyl-benzofuran-3-ca- rboxylic acid
benzyl-(5-bromo-6-hydroxy-naphthalen-2-ylmethyl)-amide (0.60 g,
100%) was isolated as a light yellow foam, MS m/z: 542
[M+H].sup.+.
[0438] Elemental Analysis for C.sub.31H.sub.28BrNO.sub.3 Calc'd: C,
68.64; H, 5.20; N, 2.58 Found: C, 67.92; H, 5.25; N, 2.39
[0439] Step 6: 2-Butyl-benzofuran-3-carboxylic acid
benzyl-(5-bromo-6-cyanomethoxy-naphthalen-2-ylmethyl)-amide.
Prepared in the same manner as described in step 4 of Example 32.
The crude material was chromatographed on 50 g silica gel (230-400
mesh) using 0-5% ethyl acetate in methylene chloride as the eluent.
Isolation of the desired component gave
2-butyl-benzofuran-3-carboxylic acid
benzyl-(5-bromo-6-cyanomethoxy-naphthalen-2-ylmethyl)-amide (0.33
g, 81%) as a tan solid, mp 105-110.degree. C.
[0440] Elemental Analysis for C.sub.33H.sub.29BrN.sub.2O.sub.3
Calc'd: C, 68.15; H, 5.03; N, 4.82 Found: C, 67.95; H, 4.82; N,
4.79
[0441] Step 7: 2-Butyl-benzofuran-3-carboxylic acid
benzyl-[5-bromo-6-(1H-tetrazol-5-ylmethoxy)-naphthalen-2-ylmethyl]-amide.
Prepared in the same manner as described in step 5 of Example 32,
the title compound was isolated as a tan foam (0.18 g, 65%), MS
m/z: 624 [M+H].sup.+.
[0442] Elemental Analysis for C.sub.33H.sub.30BrN.sub.5O.sub.3+0.17
H.sub.2O Calc'd: C, 63.1 6; H, 4.87; N, 11.16 Found: C, 61.88; H,
5.26; N, 11.10
EXAMPLE 49
2-Methyl-benzofuran-3-carboxylic acid
benzyl-[5-bromo-6-(1H-tetrazol-5-ylm-
ethoxy)-naphthalen-2-ylmethyl]-amide
[0443] Step 1: 2-Methyl-benzofuran-3-carboxylic acid
benzyl-(6-hydroxy-naphthalen-2ylmethyl)-amide. Prepared in the same
manner as described in step 2 of Example 32, and replacing
2-ethyl-benzofuran-3-carbonyl chloride with
2-methyl-benzofuran-3-carbony- l chloride, prepared in step 2 of
Example 20 and 6-methylaminomethyl-napht- halen-2-ol with
6-(benzylamino-methyl)-naphthalen-2-ol, prepared in step 3 of
Example 48. Chromatography of the crude oil on 400 g silica gel
(230-400 mesh) using 2-3% ethyl acetate in methylene chloride as
the eluent gave 2-methyl-benzofuran-3-carboxylic acid
benzyl-(6-hydroxy-napht- halen-2ylmethyl)-amide (0.71 g, 30%) as a
yellow solid, mp 190-193.degree. C.
[0444] Elemental Analysis for C.sub.28H.sub.23NO.sub.3 Calc'd: C,
79.79; H, 5.50; N, 3.32 Found: C, 79.14; H, 5.65; N, 2.89
[0445] Step 2: 2-Methyl-benzofuran-3-carboxylic acid
benzyl-(5-bromo-6-hydroxy-naphthalen-2ylmethyl)-amide. Prepared in
the same manner as described in step 3 of Example 32. The crude oil
was crystallized with hexane and then recrystallized from
isopropanol. Light yellow crystals were collected by filtration and
dried under reduced pressure to give 1.0 g (69%) of
2-methyl-benzofuran-3-carboxylic acid
benzyl-(5-bromo-6-hydroxy-naphthalen-2ylmethyl)-amide, mp
184-185.degree. C.
[0446] Elemental Analysis for C.sub.28H.sub.22BrNO.sub.3 Calc'd: C,
67.21; H, 4.43; N, 2.80 Found: C, 67.08; H, 4.39; N, 2.71
[0447] Step 3: 2-Methyl-benzofuran-3-carboxylic acid
benzyl-(5-bromo-6-cyanomethoxy-naphthalen-2ylmethyl)-amide.
Prepared in the same manner as described in step 4 of Example 32.
The crude oil was crystallized with hexane and ethyl acetate and
dried under reduced pressure to give
2-methyl-benzofuran-3-carboxylic acid
benzyl-(5-bromo-6-cyanomethoxy-naphthalen-2ylmethyl)-amide (0.423
g, 98%) as a tan solid, mp 145-146.degree. C.
[0448] Elemental Analysis for C.sub.30H.sub.23BrN.sub.2O.sub.3
Calc'd: C, 66.80; H, 4.30; N, 5.19 Found: C, 66.57; H, 4.48; N,
5.23
[0449] Step 4: 2-Methyl-benzofuran-3-carboxylic acid
benzyl-[5-bromo-6-(1H-tetrazol-5-ylmethoxy)-naphthalen-2-ylmethyl]-amide.
In the same manner as described in step 7 of Example 31, the title
compound (0.13 g, 48%) was isolated as a tan foam, MS m/z: 582
[M+H].sup.+.
[0450] Elemental Analysis for C.sub.30H.sub.24BrN.sub.5O.sub.3
Calc'd: C, 61.65; H, 4.18; N, 11.98 Found: C, 60.52; H, 4.58; N,
11.38
EXAMPLE 50
2-Ethyl-benzofuran-3-carboxylic acid
benzyl-[5-bromo-6-(1H-tetrazol-5ylmet-
hoxy)-naphthalen-2-ylmethyl)-amide
[0451] Step 1: 2-Ethyl-benzofuran-3-carboxylic acid
benzyl-(6-hydroxy-naphthalen-2ylmethyl)-amide. Prepared in the same
manner as described in step 2 of Example 32, and replacing
6-methylaminomethyl-naphthalen-2-ol with
6-(benzylamino-methyl)-naphthale- n-2-ol, prepared in step 3 of
Example 48. The crude oil was purified by chromatography on 500 g
of silica gel (230-400 mesh) using 5% ethyl acetate in methylene
chloride as the eluent. Isolation of the desired product gave
2-ethyl-benzofuran-3-carboxylic acid benzyl-(6-hydroxy-napht-
halen-2-ylmethyl)-amide (1.9 g, 83%) as a yellow oil, MS m/z: 436
[M+H].sup.+.
[0452] Elemental Analysis for C.sub.29H.sub.25NO.sub.3+0.65
C.sub.4H.sub.8O.sub.2 Calc'd: C, 77.02; H, 6.18; N, 2.84 Found: C,
76.88; H, 5.99; N, 2.82
[0453] Step 2: 2-Ethyl-benzofuran-3-carboxylic acid
benzyl-(5-bromo-6-hydroxy-naphthalen-2-ylmethyl)-amide. Prepared in
the same manner as described in step 3 of Example 32. The crude
yellow solid was purified by recrystallization from a minimum
amount of ethyl acetate. The crystals were collected by filtration
and dried under reduced pressure to give
2-ethyl-benzofuran-3-carboxylic acid
benzyl-(5-bromo-6-hydroxy-naphthalen-2-ylmethyl)-amide (1.1 g, 60%)
as light yellow crystals, mp 125-130.degree. C.
[0454] Elemental Analysis for C.sub.29H.sub.24BrNO.sub.3 Calc'd: C,
67.71; H, 4.70; N, 2.72 Found: C, 67.56; H, 4.77; N, 2.61
[0455] Step 3: 2-Ethyl-benzofuran-3-carboxylic acid
benzyl-(5-bromo-6-cyanomethoxy-naphthalen-2-ylmethyl)-amide.
Prepared in the same manner as described in step 4 of Example 32.
The crude product was dried under reduced pressure to give
2-ethyl-benzofuran-3-carboxylic acid
benzyl-(5-bromo-6-cyanomethoxy-naphthalen-2-ylmethyl)-amide (0.394
g, 92%) as a tan solid, mp 92-100.degree. C.
[0456] Elemental Analysis for C.sub.31H.sub.25BrN.sub.2O.sub.3
Calc'd: C, 67.28; H, 4.55; N, 5.06 Found: C, 67.22; H, 4.75; N,
5.07
[0457] Step 4: 2-Ethyl-benzofuran-3-carboxylic acid
benzyl-[5-bromo-6-(1H-tetrazol-5ylmethoxy)-naphthalen-2-ylmethyl)-amide.
Prepared in the same manner as described in step 7 of Example 31.
The title compound was isolated as a tan foam (0.21 g, 78%), MS
m/z: 596 [M+H].sup.+.
[0458] Elemental Analysis for C.sub.31H.sub.26BrN.sub.5O.sub.3+0.08
H.sub.2O Calc'd: C, 62.27; H, 4.41; N, 11.71 Found: C, 61.32; H,
4.71; N, 11.05
EXAMPLE 51
2-Butyl-benzofuran-3-carboxylic acid
[5-bromo-6-(1H-tetrazol-5-ylmethoxy)--
naphthalen-2-ylmethyl]-butyl-amide
[0459] Step 1: Butyl-(6-methoxy-naphthalen-2-ylmethylene)-amine.
Prepared in the same manner as described in step 1 of Example 48
and replacing benzylamine with butylamine gave
butyl-(6-methoxy-naphthalen-2-ylmethylen- e)-amine (12.1 g, 93%) as
a yellow solid, MS m/z: 242 [M+H].sup.+.
[0460] Elemental Analysis for C.sub.16H.sub.19NO Calc'd: C, 79.60;
H, 7.94; N, 5.80 Found: C, 78.97; H, 7.88; N, 5.66
[0461] Step 2: Butyl-(6-methoxy-naphthalen-2-ylmethyl)-amine.
Prepared in the same manner as described in step 2 of Example 48,
butyl-(6-methoxy-naphthalen-2-ylmethyl)-amine (10.65 g, 87.6%) was
isolated as an off white solid, mp 55-80.degree. C.
[0462] Elemental Analysis for C.sub.16H.sub.21NO Calc'd: C, 78.97;
H, 8.70; N, 5.76 Found: C, 78.53; H, 8.73; N, 5.53
[0463] Step 3: 6-Butylaminomethyl-naphthalen-2-ol. A mixture of
butyl-(6-methoxy-naphthalen-2-ylmethyl)-amine (10.0 g, 41.09 mmol),
prepared in the previous step, 300 mL of 48% HBr and 200 mL of
glacial acetic acid was refluxed under nitrogen for 19 h
(overnight). The solvent was removed under reduced pressure. The
resulting residue was partitioned between ethyl acetate and 5%
sodium bicarbonate. The organic layer was separated, dried
(MgSO.sub.4) and the solvent removed under reduced pressure to give
6-butylaminomethyl-naphthalen-2-ol (7.54 g, 80%) as a brown solid,
mp 108-112.degree. C.
[0464] Elemental Analysis for C.sub.15H.sub.19NO Calc'd: C, 78.56;
H, 8.35; N, 6.11 Found: C, 73.43; H, 7.76; N, 5.56
[0465] Step 4: 2-Butyl-benzofuran-3-carboxylic acid
butyl-(6-hydroxy-naphthalen-2-ylmethyl)-amide. Prepared in the same
manner as described in step 4 of Example 48, and replacing
6-(benzylamino-methyl)-naphthalen-2-ol with
6-butylaminomethyl-naphthalen- -2-ol, prepared in the previous
step, gave 2-butyl-benzofuran-3-carboxylic acid
butyl-(6-hydroxy-naphthalen-2-ylmethyl)-amide as a brown oil, MS
m/z: 430 [M+H].sup.+.
[0466] Elemental Analysis for C.sub.28H.sub.31NO.sub.3 Calc'd: C,
78.29; H, 7.27; N, 3.26 Found: C, 77.45; H, 7.15; N, 2.63
[0467] Step 5: 2-Butyl-benzofuran-3-carboxylic acid
(5-bromo-6-hydroxy-naphthalen-2-ylmethyl)-butyl-amide. A solution
of bromine (0.193 mL, 3.748 mmol) in 50 mL of glacial acetic acid
was added dropwise under nitrogen to a solution of
2-butyl-benzofuran-3-carboxylic acid
butyl-(6-hydroxy-naphthalen-2-ylmethyl)-amide (1.61 g, 3.748 mmol),
prepared in the previous step, in 150 mL of glacial acetic acid at
room temperature. The reaction was stirred at room temperature for
18 h. The solvent was removed under reduced pressure. The resulting
residue was made basic with 5% NaHCO.sub.3 and extracted five times
with ethyl acetate. The organic layer was dried (MgSO.sub.4) and
the solvent removed under reduced pressure to give 1.83 g of a
brown foam. The foam was chromatographed on 400 g of silica gel
(230-400 mesh) using 0-2% ethyl acetate in methylene chloride as
the eluent. Isolation of the desired material gave
2-butyl-benzofuran-3-carboxylic acid
(5-bromo-6-hydroxy-naphthalen-2-ylmethyl)-butyl-amide (0.9549 g,
50%) as a tan foam, MS m/z: 508 [M+H].sup.+.
[0468] Elemental Analysis for C.sub.28H.sub.30BrNO.sub.3 Calc'd: C,
66.14; H, 5.95; N, 2.75 Found: C, 66.44; H, 5.98; N, 2.65
[0469] Step 6: 2-Butyl-benzofuran-3-carboxylic acid
(5-bromo-6-cyanomethoxy-naphthalen-2-ylmethyl)-butyl-amide. In the
same manner as described in step 4 of Example 32,
2-butyl-benzofuran-3-carboxy- lic acid
(5-bromo-6-cyanomethoxy-naphthalen-2-ylmethyl)-butyl-amide (0.530
g, 99%) was isolated as a brown foam, MS m/z: 547 [M+H].sup.+.
[0470] Elemental Analysis for C.sub.30H.sub.31BrN.sub.2O.sub.3
Calc'd: C, 65.01; H, 5.71; N, 5.12 Found: C, 65.55; H, 5.80; N,
5.22
[0471] Step 7: 2-Butyl-benzofuran-3-carboxylic acid
[5-bromo-6-(1H-tetrazol-5-ylmethoxy)-naphthalen-2-ylmethyl]-butyl-amide.
A mixture of 2-butyl-benzofuran-3-carboxylic acid
(5-bromo-6-cyanomethoxy- -naphthalen-2-ylmethyl)-butyl-amide (0.285
g, 0.52 mmol), prepared in the previous step, sodium azide (0.101
g, 1.56 mmol) and ammonium chloride (0.083 g, 1.56 mmol) in 10 mL
of anhydrous DMF was stirred at 100.degree. C. under nitrogen for 5
h. By TLC starting material remained. Additional amounts of sodium
azide (0.101 g, 1.56 mmol) and ammonium chloride (0.083 g, 1.56
mmol) were added and the reaction stirred at 100.degree. C. under
nitrogen for 3 h. The reaction was diluted with water, made basic
with 1N NaOH and extracted five times with ethyl acetate. The
organic layer was separated and acidified with 1N HCl. The solvent
was removed under reduced pressure and the residue diluted with 10
mL of water. A solid foam formed, which was collected by filtration
and dried under reduced pressure to give the title compound (0.2765
g, 90%) as a tan foam, MS m/z: 588 [M-H].sup.-.
[0472] Elemental Analysis for C.sub.30H.sub.32BrN.sub.5O.sub.3+0.32
H.sub.2O Calc'd: C, 60.43; H, 5.52; N, 11.75 Found: C, 60.44; H,
5.46; N, 11.41
EXAMPLE 52
2-Methyl-benzofuran-3-carboxylic acid
[5-bromo-6-(1H-tetrazol-5-ylmethoxy)-
-naphthalen-2-ylmethyl]-butyl-amide
[0473] Step 1: 2-Methyl-benzofuran-3-carboxylic acid
butyl-(6-hydroxy-naphthalen-2-ylmethyl)-amide. Prepared in the same
manner as described in step 4 of Example 48 and replacing
6-(benzylamino-methyl)-naphthalen-2-ol with
6-butylaminomethyl-naphthalen- -2-ol, prepared in step 3 of Example
51, and replacing 2-butyl-benzofuran-3-carbonyl chloride with
2-methy-benzofuran-3-carbonyl chloride, prepared in step 2 of
Example 20. Purification of the crude product on 300 g silica gel
(230-400 mesh) using 25%-33% ethyl acetate in hexane as the eluent
gave 2-methyl-benzofuran-3-carboxylic acid
butyl-(6-hydroxy-naphthalen-2-ylmethyl)-amide (1.03 g, 47%) as a
tan solid, mp 126-128.degree. C.
[0474] Elemental Analysis for C.sub.25H.sub.25NO.sub.3 Calc'd: C,
77.49; H, 6.50; N, 3.61 Found: C, 77.69; H, 6.43; N, 3.57
[0475] Step 2: 2-Methyl-benzofuran-3-carboxylic acid
(5-bromo-6-hydroxy-naphthalen-2-ylmethyl)-butyl-amide. In the same
manner as described in step 5 of Example 51,
2-methyl-benzofuran-3-carboxylic acid
(5-bromo-6-hydroxy-naphthalen-2-ylmethyl)-butyl-amide (1.1176 g,
99%) was isolated as an off-white foam, MS m/z: 464
[M-H].sup.-.
[0476] Elemental Analysis for C.sub.25H.sub.24BrNO.sub.3 Calc'd: C,
64.38; H, 5.19; N, 3.00 Found: C, 63.99; H, 5.19; N, 2.86
[0477] Step 3: 2-Methyl-benzofuran-3-carboxylic acid
(5-bromo-6-cyanomethoxy-naphthalen-2-ylmethyl)-butyl-amide.
Prepared in the same manner as described in step 4 of Example 32.
The crude material was chromatographed on 200 g of silica gel
(230-400 mesh) using 0%-2% ethyl acetate in methylene chloride as
the eluent. Isolation of the desired material gave
2-methyl-benzofuran-3-carboxylic acid
(5-bromo-6-cyanomethoxy-naphthalen-2-ylmethyl)-butyl-amide (0.41 g,
76%) as a white foam, MS m/z: 505 [M+H].sup.+.
[0478] Elemental Analysis for C.sub.27H.sub.25BrN.sub.2O.sub.3
Calc'd: C, 64.16; H, 4.99; N, 5.54 Found: C, 63.86; H, 4.86; N,
5.35
[0479] Step 4: 2-Methyl-benzofuran-3-carboxylic acid
[5-bromo-6-(1H-tetrazol-5-ylmethoxy)-naphthalen-2-ylmethyl]-butyl-amide.
In the same manner as described in step 7 of Example 51, the title
compound (0.22 g, 67%) was isolated as an off-white solid, mp
204-206.degree. C.
[0480] Elemental Analysis for C.sub.27H.sub.26BrN.sub.5O.sub.3+0.04
H.sub.2O Calc'd: C, 59.05; H, 4.79; N, 12.75 Found: C, 58.73; H,
4.86; N, 12.47
EXAMPLE 53
2-[1-Bromo-6-({[5-(3,5-dichloro-phenoxy)-furan-2-carbonyl]-amino}-methyl)--
naphthalen-2-yloxy]-3-phenyl-propionic acid
[0481] Step 1: (5-Bromo-6-hydroxy-naphthalen-2-ylmethyl)-carbamic
acid tert-butyl ester. A solution of benzyltrimethylammoniumbromide
(1.755 g, 4.5 mmol) in 50 mL of methylene chloride was added
dropwise under nitrogen over 2 h to a mixture of
(6-hydroxy-naphthalen-2-ylmethyl)-carba- mic acid tert-butyl ester
(1.24 g, 4.5 mmol), prepared in step 1 of Example 13, and calcium
carbonate (1.35 g, 13.5 mmol) in 150 mL of methylene chloride plus
60 mL of methanol. The reaction was stirred for 20 h (overnight).
The reaction was diluted with water and extracted three times with
methylene chloride. The organic extracts were combined, dried
(MgSO.sub.4) and the solvent removed under reduced pressure to give
1.4 g of a yellow solid. The solid was recrystallized from 15 mL of
isopropanol. The crystals were collected by filtration and dried
under reduced pressure to give
(5-bromo-6-hydroxy-naphthalen-2-ylmethyl)-carbam- ic acid
tert-butyl ester (0.95 g, 60%) as an off white solid, mp
150-152.degree. C.
[0482] Elemental Analysis for C.sub.16H.sub.18BrNO.sub.3 Calc'd: C,
54,56; H, 5.15; N, 3.98 Found: C, 54.22; H, 4.84; N, 3.82
[0483] Step 2:
2-[1-Bromo-6-(tert-butoxycarbonylamino-methyl)-naphthalen-y-
loxy]-3-phenyl-propionic acid methyl ester. A solution of
3-phenyl-2-trifluoromethanesulfonyloxy-propionic acid methyl ester
(5.0 g, 16 mmol), prepared in step 2 of Example 7, in 25 mL of
acetone was added under nitrogen to a mixture of
(5-bromo-6-hydroxy-naphthalen-2-ylme- thyl)-carbamic acid
tert-butyl ester (3.7 g, 10.5 mmol), prepared in the previous step,
and cesium carbonate (6.84 g, 21 mmol) in 100 mL of acetone at room
temperature. The reaction was stirred for 17 h (overnight). The
solvent was removed under reduced pressure and the residue was
diluted with water and extracted three times with ethyl acetate.
The organic extracts were combined, dried (MgSO.sub.4) and the
solvent removed under reduced pressure to give 6 g of a yellow
solid. The solid was chromatographed on 600 g of silica gel
(230-400 mesh) using 5% ethyl acetate in methylene chloride as the
eluent. Isolation of the desired material gave
2-[1-bromo-6-(tert-butoxycarbonylamino-methyl)-naph-
thalen-yloxy]-3-phenyl-propionic acid methyl ester (4.02 g, 74%) as
a white solid.
[0484] Elemental Analysis for C.sub.26H.sub.28BrNO.sub.5 Calc'd: C,
60.71; H, 5.49; N, 2.72 Found: C, 61.10; H, 5.55; N, 2.50
[0485] Step 3:
5-Bromo-6-(1-methoxycarbonyl-2-phenyl-ethoxy)-naphthalen-2--
ylmethyl-ammonium; chloride. A solution of 50 mL of ethyl acetate
saturated with HCl gas was added under nitrogen to
2-[1-bromo-6-(tert-butoxycarbonylamino-methyl)-naphthalen-yloxy]-3-phenyl-
-propionic acid methyl ester (2.0 g, 3.888 mmol), prepared in the
previous step. A precipitate formed within 0.5 h. The reaction
stirred for 19 h (overnight). The solid was collected by
filtration, rinsed two times with ethyl acetate and dried under
reduced pressure to give
5-bromo-6-(1-methoxycarbonyl-2-phenyl-ethoxy)-naphthalen-2-ylmethyl-ammon-
ium; chloride (1.3, 72%) as an off-white solid, MS m/z: 414
[M+H]+.
[0486] Elemental Analysis for C.sub.21H.sub.20BrNO.sub.3+HCl
Calc'd: C, 55.96; H, 4.70; N, 3.11 Found: C, 56.18; H, 4.66; N,
3.08
[0487] Step 4:
2-[1-Bromo-6-({[5-(3,5-dichloro-phenoxy)-furan-2-carbonyl]--
amino}-methyl)-naphthalen-2-yloxy]-3-phenyl-propionic acid methyl
ester. 5-(3,5-Dichloro-phenoxy)-furan-2-carbonyl chloride (0.194 g,
0.6655 mmol) was added under nitrogen to a suspension of
5-bromo-6-(1-methoxycarbonyl--
2phenyl-ethoxy)-naphthalen-2-ylmethyl-ammonium; chloride (0.30 g,
0.6655 mmol), prepared in the previous step, in 20 mL of methylene
chloride at room temperature. Triethylamine (0.186 mL, 1.33 mmol)
was then added to the mixture. The reaction was stirred at room
temperature for 18 h (overnight). The reaction was diluted with
methylene chloride, extracted one time with 1N HCl and two times
with 5% NaHCO.sub.3. The organic layer was separated, dried
(MgSO.sub.4) and the solvent removed under reduced pressure to give
2-[1-bromo-6-({[5-(3,5-dichloro-phenoxy)-furan-2-carbony-
l]-amino}-methyl)-naphthalen-2-yloxy]-3-phenyl-propionic acid
methyl ester (0.4079 g, 92%) as a tan oil, MS m/z: 668 [M+H]+.
[0488] Elemental Analysis for C.sub.32H.sub.24BrCl.sub.2NO.sub.6
Calc'd: C, 57.42; H, 3.61; N, 2.09 Found: C, 57.26; H, 3.45; N,
2.07
[0489] Step 5:
2-[1-Bromo-6-({[5-(3,5-dichloro-phenoxy)-furan-2-carbonyl]--
amino}-methyl)-naphthalen-2-yloxy]-3-phenyl-propionic acid. A
mixture of
2-[1-bromo-6-({[5-(3,5-dichloro-phenoxy)-furan-2-carbonyl]-amino}-methyl)-
-naphthalen-2-yloxy]-3-phenyl-propionic acid methyl ester (0.34 g,
0.508 mmol), prepared in the previous step, 1N NaOH (1.50 mL, 1.5
mmol), 5 mL of water and 50 mL of methanol was stirred under
nitrogen at room temperature for 18 h (overnight). The methanol was
removed under reduced pressure. The solid that formed was collected
by filtration and identified as the sodium salt salt of
2-[1-bromo-6-({[5-(3,5-dichloro-phe-
noxy)-furan-2-carbonyl]-amino}-methyl)-naphthalen-2-yloxy]-3-phenyl-propio-
nic acid (0.1537 g, 46%). The clear filtrate was acidified with 1N
HCl. The solid that precipitated was collected by filtration and
dried under reduced pressure to give the title compound (0.0905 g,
27%) as a white solid, mp 86-100.degree. C.
[0490] Elemental Analysis for
C.sub.31H.sub.22NO.sub.6Cl.sub.2Br+0.32 H.sub.2O Calc'd: C, 56.32;
H, 3.45; N, 2.12 Found: C, 56.09; H, 3.35; N, 2.09
EXAMPLE 54
2-(1-Bromo-6-{[(1-phenyl-5-propyl-1H-pyrazole-4-carbonyl)-amino]-methyl}-n-
aphthalen-2-yloxy)-3-phenyl-propionic acid
[0491] In the same manner as described in Example 53, the title
compound was isolated as a white solid, MS m/z: 612 [M+H]+.
[0492] Elemental Analysis for C.sub.33H.sub.30BrN.sub.3O.sub.4+0.49
H.sub.2O Calc'd: C, 63.79; H, 5.03; N, 6.76 Found: C, 63.82; H,
4.93; N, 6.84
EXAMPLE 55
2-{1-Bromo-6-[4-cyclohexyl-benzoylamino)-methyl]-naphthalen-2-yloxy}-3-phe-
nyl-propionic acid
[0493] Step 1:
2-{1-Bromo-6-[(4-cyclohexyl-benzoylamino)-methyl]-naphthale-
n-2-yloxy}-3-phenyl-propionic acid methyl ester.
4-Cyclohexyl-benzoyl chloride (0.67 mmol) was added under nitrogen
to a suspension of
5-bromo-6-(1-methoxycarbonyl-2-phenyl-ethoxy)-naphthalen-2-ylmethyl-ammon-
ium; chloride (0.30 g, 0.67 mmol), prepared in step 3 of Example
53, in 20 mL of methylene chloride at room temperature.
Triethylamine (0.186 mL, 1.33 mmol) was then added to the mixture.
After the addition the reaction was stirred at room temperature for
18 h (overnight). The reaction was diluted with methylene chloride,
extracted one time with 1N HCl and two times with 5% NaHCO.sub.3.
The organic layer was separated, dried (MgSO.sub.4) and the solvent
removed under reduced pressure to give
2-{1-bromo-6-[(4-cyclohexyl-benzoylamino)-methyl]-naphthalen-2-yloxyl}-3--
phenyl-propionic acid methyl ester (0.3362 g, 84%) as an off-white
solid, mp 160-161.degree. C.
[0494] Elemental Analysis for C.sub.34H.sub.34BrNO.sub.4 Calc'd: C,
68.00; H, 5.71; N, 2.33 Found: C, 67.67; H, 5.55; N, 2.29
[0495] Step 2:
2-{1-Bromo-6-[4-cyclohexyl-benzoylamino)-methyl]-naphthalen-
-2-yloxy}-3-phenyl-propionic acid. A mixture of
2-{1-bromo-6-[(4-cyclohexy-
l-benzoylamino)-methyl]-naphthalen-2-yloxy}-3-phenyl-propionic acid
methyl ester (0.2174 g, 0.362 mmol), prepared in the previous step,
1N NaOH (1.0 mL, 1.0 mmol), 5 mL of H.sub.2O and 100 mL of methanol
was refluxed under nitrogen for 5 h. The reaction was cooled to
room temperature and acidified with 1N HCl. The methanol was
removed under reduced pressure. The solid that precipitated was
collected by filtration, washed two times with water and dried
under reduced pressure to give the title compound (0.1506 g, 71%)
as a white solid, mp 179-182.degree. C.
[0496] Elemental Analysis for
C.sub.31H.sub.22NO.sub.6Cl.sub.2Br+0.32 H.sub.2O Calc'd: C, 56.32;
H, 3.45; N, 2.12 Found: C, 56.09; H, 3.35; N, 2.09
EXAMPLE 56
2-{1-Bromo-6-[(3,5-di-tert-butyl-benzoylamino)-methyl]-naphthalen-2-yloxy}-
-3-phenyl-propionic acid
[0497] In the same manner as described in Example 55, the title
compound was isolated as a white solid, mp 160-163.degree. C.
[0498] Elemental Analysis for C.sub.35H.sub.38BrNO.sub.4+0.3
H.sub.2O Calc'd: C, 67.59; H, 6.26; N, 2.25 Found: C, 67.57; H,
6.18; N, 2.32
EXAMPLE 57
2-{1-Bromo-6-[(3-phenoxy-benzoylamino)-methyl]-naphthalen-2-yloxy}-3-pheny-
l-propionic acid
[0499] In the same manner as described in Example 55, the title
compound was isolated as a white solid, MS m/z: 596 [M+H]+.
[0500] Elemental Analysis for C.sub.33H.sub.26BrNO.sub.5+0.33
H.sub.2O. Calc'd: C, 65.79; H, 4.46; N, 2.33 Found: C, 63.84; H,
4.36; N, 2.22
EXAMPLE 58
2-(1-Bromo-6-{[(2-ethyl-benzofuran-3-carbonyl)-amino]-methyl}-naphthalen-2-
-yloxy)-3-phenyl-propionic acid
[0501] Step 1:
2-(1-Bromo-6-{[(2-ethyl-benzofuran-3-carbonyl)-amino]-methy-
l}-naphthalen-2-yloxy)-3-phenyl-propionic acid methyl ester.
2-Ethyl-benzofuran-3-carbonyl chloride (0.444 mmol), prepared in
step 2 of Example 21, was added under nitrogen to a suspension of
5-bromo-6-(1-methoxycarbonyl-2-phenyl-ethoxy)-naphthalen-2-ylmethyl-ammon-
ium; chloride (0.200 g, 0.444 mmol), prepared in step 3 of Example
53, in 20 mL of methylene chloride. Triethylamine (0.124 mL, 0.888
mmol) was then added to the mixture. The reaction was stirred at
room temperature for 18 h (overnight). The reaction was diluted
with methylene chloride, extracted one time with 1N HCl and two
times with 5% sodium bicarbonate. The organic layer was separated,
dried (MgSO.sub.4) and the solvent removed under reduced pressure
to give 2-(1-bromo-6-{[(2-ethyl-benzofuran-
-3-carbonyl)-amino]-methyl}-naphthalen-2-yloxy)-3-phenyl-propionic
acid methyl ester (0.27 g, 100%) as a tan solid, mp 139-143.degree.
C.
[0502] Elemental Analysis for C.sub.32H.sub.28BrNO.sub.5 Calc'd: C,
65.54; H, 4.81; N, 2.39 Found: C, 64.94; H, 4.78; N, 2.38
[0503] Step 2:
2-(1-Bromo-6-{[(2-ethyl-benzofuran-3-carbonyl)-amino]-methy-
l}-naphthalen-2-yloxy)-3-phenyl-propionic acid. A mixture of
2-(1-bromo-6-{[(2-ethyl-benzofuran-3-carbonyl)-amino]-methyl}-naphthalen--
2-yloxy)-3-phenyl-propionic acid methyl ester (0.200 g, 0.341
mmol), prepared in the previous step, 1N NaOH (1.02 mL, 1.02 mmol),
10 mL of water and 100 mL of methanol was stirred under nitrogen at
room temperature for 20 h (overnight). The reaction was acidified
with 1N HCl until acidic by litmus paper. The methanol was removed
under reduced pressure. The solid that precipitated and was
collected by filtration and dried under reduced pressure to give
the title compound (0.0576 g, 29%) as a white solid, mp
162-165.degree. C.
[0504] Elemental Analysis for C.sub.31H.sub.26BrNO.sub.5+0.15 mol
H.sub.2O Calc'd: C, 64.74; H, 4.61; N, 2.44 Found: C, 64.73; H,
4.40; N, 2.37
EXAMPLE 59
2-[1-Bromo-6-({[1-4-chloro-phenyl)-cyclopentanecarbonyl]-amino}-methyl)-na-
phthalen-2-yloxy]-3-phenyl-propionic acid
[0505] In the same manner as described in Example 58, the title
compound was isolated as a white solid, mp 207-208.degree. C.
[0506] Elemental Analysis for C.sub.32H.sub.29BrClNO.sub.4+0.06
H.sub.2O Calc'd: C, 63.21; H, 4.83; N, 2.30 Found: C, 63.11; H,
4.71; N, 2.28
EXAMPLE 60
2-Bromo-6-({[5-(3-trifluoromethyl-phenyl)-furan-2-carbonyl]-amino}-methyl)-
-naphthalen-2-yloxy]-3-phenyl-propionic acid
[0507] In the same manner as desdribed in Example 58, the title
compound was isolated as a white solid, MS m/z: 636
[M-H].sup.-.
[0508] Elemental Analysis for
C.sub.32H.sub.23BrF.sub.3NO.sub.5+0.22 H.sub.2O Calc'd: C, 59.83;
H, 3.86; N, 2.18 Found: C, 59.50; H, 3.55; N, 2.14
[0509] General Experimental for Examples 61 to 72
[0510] Amine A:
(5-Bromo-6-methoxy-naphthalen-2-ylmethyl)-methyl-amine. Prepared in
step 7 of Example 36.
[0511] Amine B:
Benzyl-(5-bromo-6-methoxy-naphthalen-2-ylmethyl)-amine. Prepared in
the same manner as described Example 36 and substituting
benzylamine for methylamine.
[0512] General Procedure for the Acylation of Amine A and Amine B.
The acid chlorides were either commercially available or prepared
as described in step 2 of Example 3. To a stirred solution of
either Amine A or Amine B (2 mmol) and triethylamine (2.5 mmol) in
CH.sub.2Cl.sub.2 (10 mL) was added a solution of the acid chloride
(2.1 mmol) in CH.sub.2Cl.sub.2 (5 mL). The reactions were allowed
to sit at room temperature for 6 h. Aqueous NaHCO.sub.3 was added
and the mixture was extracted with CH.sub.2Cl.sub.2 (3.times.20
mL). The combined organic phases were dried (Na.sub.2SO.sub.4),
filtered and concentrated. The products were used in the next step
without further purification.
EXAMPLE 61
2-(1-Bromo-6-{[(4cyclohexyl-benzoyl)-methyl-amino]-methyl}-naphthalen-2-yl-
oxy)-3-phenyl-propionic acid
[0513] Step 1:
N-(5Bromo-6-hydroxy-naphthalen-2-ylmethyl)-4-cyclohexyl-N-m-
ethyl-benzamide. Boron trichloride (5.5 mL of a 1 M solution in
methylene chloride; 5.5 mmol) was added under argon to a solution
of
N-(5-bromo-6-methoxy-naphthalen-2-ylmethyl)-4-cyclohexyl-N-methyl-benzami-
de (860 mg, 1.8 mmol), prepared by the general acylation procedure
described above, and tetrabutylammonium iodide (2.04 g, 5.5 mmol)
in 10 mL of methylene chloride at dry ice-acetone temperature.
After the addition the reaction was allowed to warm to room
temperature. The reaction was considered finished after HPLC/TLC
analysis indicated the formation of a single product and the
disappearance of the starting amide. The reaction was cooled to ice
bath temperature followed by the addition of water. The organic
layer was separated and the aqueous layer extracted three times
with methylene chloride. The combined extracts were dried
(Na.sub.2SO.sub.4) and the solvent removed under reduced pressure.
The residue was purified by column chromatography (20-30% ethyl
acetate in hexanes) to give
N-(5-bromo-6-hydroxy-naphthalen-2-ylmethyl)-4-cyclohe-
xyl-N-methyl-benzamide (799 mg, 97%), LCMS (Calc'd: 451.13; Found:
451.65).
[0514] Step 2:
2-(1-Bromo-6-{[(4-cyclohexyl-benzoyl)-methyl-amino]-methyl}-
-naphthalen-2-yloxy)-3-phenyl-propionic acid methyl ester. A
mixture of
N-(5-bromo-6-hydroxy-naphthalen-2-ylmethyl)-4-cyclohexyl-N-methyl-benzami-
de (799 mg, 1.51 mmol), prepared in the previous step,
3-phenyl-2-trifluoromethanesulfonyloxypropionic acid methyl ester
(1.66 mmol), prepared in step 2 of Example 7, and cesium carbonate
(985 mg, 3.0 mmol) in acetone was stirred at room temperature for 3
h. The reaction was partitioned between water and ethyl acetate.
The aqueous layer was separated and extracted three times with
ethyl acetate. The combined extracts were dried (Na.sub.2SO.sub.4)
and the solvent removed under reduced pressure. Purification of the
residue by column chromatography using 10% -20% ethyl
acetate-hexanes as the eluent gave
2-(1-bromo-6-{[(4-cyclohexyl-benzoyl)-methyl-amino]-methyl}-naphthalen-2--
yloxy)-3-phenyl-propionic acid methyl ester (445 mg, 48%), LCMS ES+
(Calc'd: 613.2; Found: 614.3).
[0515] Step 3:
2-(1-Bromo-6-{[(4-cyclohexyl-benzoyl)-methyl-amino]-methyl}-
-naphthalen-2-yloxy)-3-phenyl-propionic acid. A mixture of
2-(1-bromo-6-{[(4-cyclohexyl-benzoyl)-methyl-amino]-methyl}-naphthalen-2--
yloxy)-3-phenyl-propionic acid methyl ester (445 mg, 0.68 mmol),
prepared in the previous step, and 0.5 mL of 10% aqueous NaOH in
THF was stirred at room temperature for 2.5 h. Aqueous 10% HCl was
added until acidic and the reaction extracted three times with
ethyl acetate. The combined extracts were dried (Na.sub.2SO.sub.4)
and the solvent removed under reduced pressure to give the title
compound (419 mg, 95%), MS m/z: 600 [M+H].sup.+.
[0516] Elemental Analysis for C.sub.34H.sub.34BrNO.sub.4 Calc'd: C,
68.00; H, 5.71; N, 2.33 Found: C, 67.24; H, 5.93; N, 2.26
[0517] Examples 62 to 72 were prepared in the same manner as
described for Example 61.
EXAMPLE 62
2-(1-Bromo-6-{[(2-butyl-benzofuran-3-carbonyl)-methyl-amino]-methyl}naphth-
alen-2-yloxy)-3-phenyl-propionic acid
[0518] MS m/z: 614 [M+H].sup.+.
[0519] Elemental Analysis for C.sub.34H.sub.32BrNO.sub.5 Calc'd: C,
66.45; H, 5.25; N, 2.28 Found: C, 59.64; H, 5.10; N, 1.73
EXAMPLE 63
2-(1-Bromo-6-{[methyl-(4'-propyl-biphenyl-4-carbonyl)-amino]-methyl}-napht-
halen-2-yloxy)-3-phenyl-propionic acid
[0520] MS m/z: 636 [M+H].sup.+.
[0521] Elemental Analysis for C.sub.37H.sub.34BrNO.sub.4 Calc'd: C,
69.81; H, 5.38; N, 2.20 Found: C, 68.77; H, 5.53; N, 2.09
EXAMPLE 64
2-[1-Bromo-6-({[5-(3,5-dichloro-phenoxy)-furan-2-carbonyl]-methyl-amino}-m-
ethyl)-naphthalen-2-yloxy]-3-phenyl-propionic acid
[0522] MS m/z: 668 [M+H].sup.+.
[0523] Elemenetal Analysis for C.sub.32H.sub.24BrCl.sub.2NO.sub.6
Calc'd: C, 57.42; H, 3.61; N, 2.09 Found: C, 57.06; H, 3.62; N,
1.92
EXAMPLE 65
2-(1-Bromo-6-{[(3,5-di-tert-butyl-benzoyl)-methyl-amino]-methyl}-naphthale-
n-2-yloxy)-3-phenyl-propionic acid
[0524] MS m/z: 630 [M+H].sup.+.
[0525] Elemental Analysis for C.sub.36H.sub.40BrNO.sub.4 Calc'd: C,
68.57; H, 6.39; N, 2.22 Found: C, 65.77; H, 6.33; N, 1.93
EXAMPLE 66
2-(1-Bromo-6-{[methyl-(1-phenyl-5-propyl-1H-pyrazole-4-carbonyl)-amino]-me-
thyl}-naphthalen-2-yloxy)-3-phenyl-propionic acid
[0526] MS m/z: 626 [M+H].sup.+.
[0527] Elemental Analysis for C.sub.34H.sub.32BrN.sub.3O.sub.4
Calc'd: C, 65.18; H, 5.15; N, 6.71 Found: C, 63.19; H, 5.91; N,
4.89
EXAMPLE 67
2-[6-({Benzyl-[5-(3,5-dichloro-phenoxy)-furan-2-carbonyl]-amino}-methyl)-1-
-bromo-naphthalen-2-yloxy]-3-phenyl-propionic acid
[0528] MS m/z: 744 [M+H].sup.+.
[0529] Elemental Analysis for C.sub.38H.sub.28BrCl.sub.2NO.sub.6
Calc'd: C, 61.23; H, 3.79; N, 1.88 Found: C, 60.57; H, 4.40; N,
1.74
EXAMPLE 68
2-(6-{[Benzyl-(2-butyl-benzofuran-3-carbonyl)-amino]-methyl}-1-bromo-napht-
halen-2-yloxy)-3-phenyl-propionic acid
[0530] MS m/z: 690 [M+H].sup.+.
[0531] Elemental Analysis for C.sub.40H.sub.36BrNO.sub.5 Calc'd: C,
69.57; H, 5.25; N, 2.03 Found: C, 65.55; H, 4.95; N, 1.58
EXAMPLE 69
2-(6-{[Benzyl-(3,5-di-tert-butyl-benzoyl)-amino]-methyl}-1-bromo-naphthale-
n-2-yloxy)-3-phenyl-propionic acid
[0532] MS m/z: 706 [M+H].sup.+.
[0533] Elemental Analysis for C.sub.42H.sub.44BrNO.sub.4 Calc'd: C,
71.38; H, 6.28; N, 1.98 Found: C, 67.64; H, 6.01; N, 1.60
EXAMPLE 70
2-(6-{[Benzyl-(4'-propyl-biphenyl-4-carbonyl)-amino]-methyl}-1-bromo-napht-
halen-2-yloxy)-3-phenyl propionic acid
[0534] MS m/z: 712 [M+H].sup.+.
[0535] Elemental Analysis for C.sub.43H.sub.38BrNO.sub.4 Calc'd: C,
72.47; H, 5.37; N, 1.97 Found: C, 71.53; H, 5.32; N, 1.71
EXAMPLE 71
2-(6-{[Benzyl-(4-cyclohexyl-benzoyl)-amino]-methyl}-1-bromo-naphthalen-2-y-
loxy-3-phenyl-propionic acid
[0536] MS m/z: 676 [M+H].sup.+.
[0537] Elemental Analysis for C.sub.40H.sub.38BrNO.sub.4 Calc'd: C,
71.00; H, 5.66; N, 2.07 Found: C, 66.13; H, 6.25; N, 1.45
EXAMPLE 72
2-(6-{[Benzyl-(1-phenyl-5-propyl-1H-pyrozole-4-carbonyl)-amino]-methyl}-1--
bromo-naphthalen-2-yloxy)-3-phenyl-propionic acid
[0538] MS m/z: 702 [M+H].sup.+.
[0539] Elemental Analysis for C.sub.40H.sub.36BrN.sub.3O.sub.4
Calc'd: C, 68.38; H, 5.16; N, 5.98 Found: C, 62.07; H, 5.52; N,
3.80
General Experimental for Examples 73 to 87
[0540] Step 1: The aryl acid (1 mmol) was charged into a 40 mL
vial. Methylene chloride (2 mL) and oxalyl chloride (131 .mu.L, 1.5
mmol) were added to the vial, followed by the addition of DMF (20
.mu.L). The vial was capped and allowed to stand at room
temperature overnight. The solvent was removed under reduced
pressure to give the acid chloride, which was used without
additional purification.
[0541] Step 2:
6-Methoxycarbonyl-methoxy-naphthalen-2-ylmethyl-ammonium; chloride.
Prepared in step 3 of Example 13.
[0542] Step 3: 6-Methoxycarbonyl-methoxy-naphthalen-2-yl-ammonium;
chloride. Prepared in a similar manner as described in step 2.
[0543] Library Procedure:
[0544] Stock Solution 1: Acid chlorides (either commercially
available or prepared as described in step 1) were dissolved in
anhydrous THF (0.25 M).
[0545] Stock Solution 2: Either
6-methoxycarbonyl-methoxy-naphthalen-2-ylm- ethyl-ammonium;
chloride or 6-methoxycarbonyl-methoxy-naphthalen-2-yl-ammo- nium;
chloride were dissolved in anhydrous THF (0.25 M).
[0546] Stock Solution 3: Anhydrous THF solution of triethylamine
(0.5 M).
[0547] To 2-dram reaction vials was added Stock Solution 2 (300
.mu.L) and Stock Solution 3 (600 .mu.L) followed by Stock Solution
1 (310 .mu.L). The vials were capped and allowed to mix at room
temperature for 48 h. The reactions were diluted with methylene
chloride (1 mL) and water (1 mL) was added. The organic phase was
removed and the aqueous phase extracted with methylene chloride
(3.times.1 mL). The methylene chloride phases were concentrated in
a clean 2-dram reaction vial. The residue was dissolved in MeOH:THF
(1:1) and 2N aqueous sodium hydroxide was added (200 .mu.L). The
vials were capped and the reactions were allowed to sit at room
temperature for 24 h, whereupon 1N aqueous HCl (500 .mu.L) was
added. The reaction mixture was extracted with methylene chloride
(3.times.1 mL). The combined organic phases were concentrated to
dryness in a tarred 2-dram vial to give the desired compounds of
Examples 73 to 87. These compounds were dissolved to a constant
concentration in DMSO (30 mM) and an aliquot (25 .mu.L) was removed
for HLPC and MS analysis.
EXAMPLE 73
(6-{[5-(2-Chloro-phenyl)-2-trifluoromethyl-furan-3-carbonyl]-amino}naphtha-
len-2-yloxy)-acetic acid
[0548] HRMS Calc'd for C.sub.24H.sub.15ClF.sub.3NO.sub.5 [M-H];
488.0518. Found: 488.05163.
EXAMPLE 74
(6-{[5-(3-Trifluoromethyl-phenyl)-furan-2-carbonyl]-amino}-naphthalen-2-yl-
oxy)-acetic acid
[0549] HRMS Calc'd for C.sub.24H.sub.16F.sub.3NO.sub.5 [M-H];
454.09078. Found: 454.09084.
EXAMPLE 75
(6-{[1-(4-Chloro-phenyl)-cyclopentanecarbonyl]-amino}-naphthalen-2-yloxy)--
acetic acid
[0550] HRMS Calc'd for C.sub.24H.sub.22ClNO.sub.4 [M-H]; 422.11646.
Found: 422.1163
EXAMPLE 76
[6-(2-Benzyloxy-benzoylamino)-naphthalen-2-yloxy]-acetic acid)
[0551] HRMS Calc'd for C.sub.26H.sub.21NO.sub.5 [M-H]; ND
EXAMPLE 77
[6-(3,5-Di-tert-butyl-benzoylamino)-naphthalen-2yl oxy]-acetic
acid
[0552] HRMS Calc'd for C.sub.27H.sub.31NO.sub.4 [M-H]; 432.21803.
Found: 432.21804.
EXAMPLE 78
{6-[(5-Biphenyl-4-yl-2-trifluoromethyl-furan-3-carbonyl)-amino]-naphthalen-
-2-yloxy}-acetic acid
[0553] HRMS Calc'd for C.sub.30H.sub.20F.sub.3NO.sub.5 [M-H];
530.12208. Found: 530.12186.
EXAMPLE 79
(6-{[1-(4-Chloro-phenyl)-cyclohexanecarbonyl]-amino}-naphathalen-2-yloxy)--
acetic acid
[0554] HRMS Calc'd for C.sub.25H.sub.24ClNO.sub.4 [M-H]; 436.13211.
Found: 436.13191
EXAMPLE 80
(6-{[1-(4-Chloro-phenyl)-cyclobutanecarbonyl]-amino}-naphthalen-2-yloxy)-a-
cetic acid
[0555] HRMS Calc'd for C.sub.23H.sub.20ClNO.sub.4 [M-H]; 408.10081.
Found: 408.10064.
EXAMPLE 81
[6-({[5-(2-Chloro-phenyl)-2-trifluoromethyl-furan-3-carbonyl]-amino}-methy-
l)-naphthalen-2-yloxy]-acetic acid
[0556] HRMS Calc'd for C.sub.25H.sub.17ClF.sub.3NO.sub.5 [M-H];
502.06745. Found: 502.06735.
EXAMPLE 82
[6-({[2-Trifluoromethyl-5-(4-trifluoromethyl-phenyl)-furan-3-carbonyl]-ami-
no}methyl)-naphthalen-2-yloxy]-acetic acid
[0557] HRMS Calc'd for C.sub.26H.sub.17F.sub.6NO.sub.5 [M-H];
536.09381. Found: 536.09381.
EXAMPLE 83
{6-[(2-Phenethyl-benzoylamino)-methyl]-naphthalen-2-yloxy}-acetic
acid
[0558] HRMS Calc'd for C.sub.28H.sub.25NO.sub.4 [M-H]; 438.17108.
Found: 438.17083.
EXAMPLE 84
[6-({[1-(4-Chloro-phenyl)-cyclopentanecarbonyl]-amino}-methyl)-naphthalen--
2-yloxy]-acetic acid
[0559] HRMS Calc'd for C.sub.25H.sub.24ClNO.sub.4 [M-H]; 436.13211.
Found: 436.13193.
EXAMPLE 85
[6-({[5-(3-Trifluoromethyl-phenyl)-furan-2-carbonyl]-amino}-methyl)-naphth-
alen-2-yloxy]-acetic acid
[0560] HRMS Calc'd for C.sub.25H.sub.18F.sub.3NO.sub.5 [M-H];
468.10643. Found: 468.10648.
EXAMPLE 86
{6-[(3,5-Di-tert-butyl-benzoylamino)methyl]-naphthalen-2-yloxy}-acetic
acid
[0561] HRMS Calc'd for C.sub.28H.sub.33NO.sub.4 [M-H]; 446.23368.
Found: 446.23367.
EXAMPLE 87
(6-{[(1-Phenyl-cyclopentanecarbonyl)-amino]-methyl}-naphthalen-2-yloxy)-ac-
etic acid
[0562] HRMS Calc'd for C.sub.25H.sub.25NO.sub.4 [M-H]; 402.17108.
Found: 402.17093.
* * * * *